Oncogenic Viruses, Volume 1: Fundamentals of Oncoviruses 0128241527, 9780128241523

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Oncogenic Viruses Volume 1 Fundamentals of Oncoviruses

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Moulay Mustapha Ennaji

Oncogenic Viruses Volume 1 Fundamentals of Oncoviruses

Edited by

Moulay Mustapha Ennaji Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2023 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-12-824152-3 For Information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisitions Editor: Kattie Washington Editorial Project Manager: Tracy I. Tufaga Production Project Manager: Swapna Srinivasan Cover Designer: Matthew Limbert Typeset by MPS Limited, Chennai, India

Contents List of Contributors About the editor Preface Acknowledgments

1.

General introduction oncogenic viruses: recent knowledge

xvii xxiii xxv xxvii

1

Moulay Mustapha Ennaji

2.

References

3

Hepatocellular carcinoma associated with hepatitis B virus and environmental factors

5

Hanaaˆ Bazir, Hlima Bessi, Mohammed Nabil Benchekroun and Moulay Mustapha Ennaji 2.1 Introduction 2.2 Hepatocellular carcinoma 2.2.1 Epidemiology and etiological factors 2.2.2 Mortality 2.3 Anatomopathological characteristics 2.3.1 Physiopathology 2.3.2 Tumor pathology 2.4 Nature and history of liver carcinogenesis 2.5 Molecular mechanism of hepatocarcinogenesis 2.6 Hepatitis B virus 2.6.1 Epidemiology 2.7 Virological data 2.7.1 The viral structure 2.7.2 Hepatitis B virus genotypes 2.7.3 The hepatitis B virus replication cycle 2.8 Natural history of hepatitis B virus infection 2.9 Antiviral treatment for hepatitis B 2.10 Hepatocellular carcinoma associated with hepatitis B virus 2.11 The link between hepatitis B virus and hepatic tumorigenesis 2.12 Molecular mechanisms of hepatocarcinogenesis induced by hepatitis B virus

5 6 6 7 7 8 8 9 10 11 11 11 11 13 13 14 15 15 16 16

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2.13 Hepatocellular carcinoma associated with environmental factors 2.14 Metabolic and environmental risk factors 2.14.1 Obesity, body mass index, and body fat 2.14.2 Hyperlipidemia 2.14.3 Diabetes 2.14.4 Tobacco 2.14.5 Alcohol 2.14.6 Lack of physical activity 2.15 Nutritional risk factors for hepatocellular carcinoma 2.15.1 Aflatoxin 2.15.2 Red meats and processed meats 2.15.3 Lipids 2.15.4 Sugary drinks and juices 2.15.5 Vitamins and minerals 2.16 Prevention of risk factors 2.17 Synergy between hepatitis B virus and environmental factors in the etiology of hepatocellular carcinoma 2.18 Conclusion Acknowledgments References

3.

General principals and mechanisms of viral oncogenic and associated cancers (cytomegalovirus, papillomaviruses, and RNA oncogenic virus)

17 17 17 17 18 18 18 19 19 19 20 20 21 21 21 22 22 23 23

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Ikram Tiabi, Said Abdallah Nabil, Berjas Abumsimir, Mohammed Nabil Benchekroun and Moulay Mustapha Ennaji

4.

29

3.1 Introduction 3.2 General information on oncogenic viruses:cytomegalovirus, papillomaviruses, and RNA oncogenic virus 3.2.1 Cytomegalovirus 3.2.2 Papillomavirus 3.2.3 RNA oncogenic virus 3.3 Conclusion Acknowledgments References

30 30 35 40 43 43 43

Infection of HPV and MMTV oncovirus in breast cancer tissues in women

49

Imane Saif, Youssef Ennaji, Mohammed El Mzibri and Moulay Mustapha Ennaji 4.1 Introduction 4.2 Infection with human papillomavirus 4.2.1 General information on human papillomavirus 4.2.2 Integration of human papillomavirus into breast cells

49 50 50 53

Contents

4.2.3 Human papillomavirus cancer 4.3 Mouse mammary tumor virus infection 4.3.1 General information on mouse mammary tumor virus 4.3.2 Integration of mouse mammary tumor virus into breast cells 4.3.3 Cancer caused by mouse mammary tumor virus 4.4 Discussion 4.5 Conclusion References Further reading

5.

MicroRNAs associated with Helicobacter pylori and Epstein-Barr virus infections in gastric cancer

vii 55 57 57 61 62 63 65 65 70

71

Fatima Ezzahra Rihane, Driss Erguibi, Farid Chehab and Moulay Mustapha Ennaji

6.

71 72 72 73 74 74 74 75 77 80

5.1 Introduction 5.2 Discovery and origin of microRNAs 5.2.1 Discovery of the first microRNA: Lin-4 5.2.2 Nomenclature of microRNA 5.3 Biogenesis of microRNAs 5.3.1 MicroRNA genomic localization 5.3.2 Primary transcripts 5.3.3 Primary transcripts maturation 5.3.4 Mechanism of action of microRNAs 5.4 MicroRNAs in gastric cancer 5.4.1 Host microRNAs associated with Helicobacter pylori infection 5.4.2 Host microRNAs associated with Epstein-Barr virus infection 5.4.3 Epstein-Barr virus-encoded microRNAs 5.5 Conclusion References

83 84 86 86

Breast cancer: epidemiology and viral ethology associated with human papillomavirus and mouse mammary tumor virus

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Patrina Joseph Iloukou Mayakia, Gervillien Arnold Malonga, Dorine Florence Luthera Ngombe Mouabata, Ghislain Loubano-Voumbi, Donatien Moukassa and Moulay Mustapha Ennaji 6.1 Introduction 6.2 Breast cancer epidemiology 6.2.1 In Africa 6.3 Risk factors for breast cancer 6.3.1 Gender 6.3.2 Personal history of breast cancer

95 96 98 98 98 99

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7.

Contents

6.3.3 Family history of breast cancer and other cancers 6.3.4 BRCA gene mutations 6.3.5 Dense breasts 6.3.6 Some genetic disorders 6.3.7 Other genetic mutations 6.4 Human papillomaviruses and mouse mammary tumor virus in breast cancer 6.4.1 Human papillomavirus 6.4.2 Mouse mammary tumor virus 6.5 Conclusion References

99 99 100 100 101 101 101 103 106 106

Human papillomavirus infections and cervical cancer

113

Samira Zoa Assoumou, Arnaud Kombe Kombe, Anicet Boumba, Tiatou Souhou, Abdou Azzaque and Moulay Mustapha Ennaji 7.1 Virology of human papillomavirus 7.1.1 Brief epidemiology and taxonomic classification 7.2 Molecular architecture of human papillomavirus and features of viral pro-oncogenes and oncoproteins 7.3 Infection cell cycle and replication 7.4 Transmission mode and risk factors 7.5 Pathophysiology, evolution, and natural history of human papillomavirus infection 7.6 Cervical cancer: a preventable disease References

8.

Covid-19 and cancer: impact on diagnosis, care and therapy

113 113 116 116 118 119 120 121

127

Said Abdallah Nabil, Berjas Abumsimir, Abdelilah Laraqui and Moulay Mustapha Ennaji 8.1 Introduction 8.2 Coronavirus disease 8.2.1 Origin of COVID-19 8.3 Factors affecting the pathogenesis of the virus 8.3.1 Gender 8.3.2 Age 8.4 The impact of the COVID-19 pandemic on cancer care 8.4.1 Chemotherapy 8.4.2 Surgery 8.4.3 Immunotherapy 8.5 The different types of anti-SARS-CoV-2 vaccine 8.6 SARS-CoV-2 vaccines in cancer patients 8.7 Conclusion Acknowledgments References

127 128 128 131 131 132 133 133 134 135 135 136 136 136 137

Contents

9.

The role of DNA oncoviruses and its association with human cancer

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Ragunath Barath, Kaviarasan Vaishak and Ramakrishnan Veerabathiran 9.1 Introduction 9.1.1 Deoxyribonucleic acid 9.1.2 Gene 9.1.3 Cancer 9.1.4 Oncogenes 9.2 History, discovery, and types 9.3 Epidemiology 9.3.1 Epstein-Barr virus 9.3.2 Human papillomavirus 9.3.3 Hepatitis B virus 9.3.4 Hepatitis C virus 9.3.5 Human T cell lymphotropic virus 1 9.3.6 Human herpesvirus 8 9.3.7 Merkel cell polyomavirus 9.4 Viral proteins involved 9.5 General mechanism by which oncovirus induces cancer in DNA 9.6 Mechanism of action for each oncoviruses 9.6.1 Epstein-Barr virus 9.6.2 Human papillomavirus 9.6.3 Hepatitis B virus 9.6.4 Human herpesvirus 8 9.6.5 Merkel cell polyomavirus 9.7 Genome and structure of viruses 9.7.1 Epstein-Barr virus 9.7.2 Human herpesvirus 8 9.7.3 Human papillomavirus 9.7.4 Merkel cell polyomavirus 9.7.5 Hepatitis B virus 9.8 Cancers associated with DNA oncoviruses 9.9 Therapeutic options for DNA oncoviruses 9.10 Conclusion Acknowledgment References

10. RNA oncoviruses and their association with cancer implications

145 145 146 146 146 146 147 147 147 148 148 149 149 149 150 150 152 152 153 154 154 156 157 157 158 158 158 158 159 160 160 162 162

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B. Ranjith, S. Sandeep and Ramakrishnan Veerabathiran 10.1 Introduction 10.1.1 Virus involvement in cancer 10.2 Oncoviruses and their variants 10.3 Timeline of oncoviruses 10.4 Endogenous and exogenous retroviruses

171 171 172 174 176

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10.5 Viral carcinogenesis 10.6 Reverse transcription and recognition of proto-oncogenes 10.6.1 Reverse transcription 10.6.2 Proto-oncogene 10.7 Human T cell lymphotropic virus 1 10.7.1 HTLV-1 epidemiology and prevalence 10.7.2 HTLV-1 etiology 10.7.3 HTLV-1 pathophysiology 10.7.4 HTLV-1 transmission 10.7.5 HTLV-1 replication 10.7.6 HTLV-1 mechanism 10.7.7 HTLV diagnosis 10.8 Hepatitis C virus 10.8.1 Hepatitis C virus epidemiology and prevalence 10.8.2 HCV etiology 10.8.3 HCV pathophysiology 10.8.4 HCV transmission 10.8.5 Hepatitis C virus pathogenesis 10.8.6 Hepatitis C virus mechanism 10.8.7 Hepatitis C virus diagnosis 10.9 Human immunodeficiency virus 10.9.1 HIV epidemiology and prevalence 10.9.2 HIV etiology 10.9.3 HIV pathophysiology 10.9.4 HIV transmission 10.9.5 HIV replication 10.9.6 Mechanisms underlying HIV-1 pathogenicity in epithelial cells 10.9.7 HIV evaluation and diagnosis 10.10 Conclusion Abbreviation Acknowledgment References

11. Evolution of viruses: tumor complications

177 178 178 178 180 180 180 181 181 182 184 185 185 185 186 186 187 188 188 189 189 189 189 189 190 190 191 193 193 193 194 194 197

Keerthana Raja, Sembiyaa Arumugam, Sheik S.S.J. Ahmed and Ramakrishnan Veerabathiran 11.1 11.2 11.3 11.4 11.5 11.6

Introduction Oncovirus and its prevalence Epidemiology Discovery of oncovirus and its timeline Mechanism of oncovirus Classification of oncoviruses 11.6.1 Epstein-Barr virus 11.6.2 Hepatitis B virus 11.6.3 Human Herpesvirus 8 11.6.4 Human papillomavirus

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Contents

11.6.5 Human T-cell lymphotropic virus 1 11.6.6 Hepatitis C virus 11.6.7 Merkel cell polyomavirus 11.7 Genes associated with oncogenes and virus tumor complications 11.7.1 Genes and their functions 11.8 Causes and prevention 11.9 Therapies and treatment 11.10 Conclusion Acknowledgment References

12. HPV oncovirus: molecular biology and mechanism of action

xi 207 207 208 210 210 212 214 216 217 217

223

My Mustaph Ennaji 12.1 Introduction 12.2 Recent progress 12.3 Discussion References

13. Oncogenic viruses and mechanism of oncogenesis: study of oncogenic characteristics of HTLV-1 and HHV-8 viruses

223 224 224 225

227

Patrina Joseph Iloukou Mayakia, Gervillien Arnold Malonga, Ragive Takale Parode, Donatien Moukassa and Moulay Mustapha Ennaji 13.1 Introduction 13.1.1 Discovery of oncogenic viruses 13.1.2 The infections concerned 13.1.3 Consequences of viral infection 13.1.4 The molecular basis of cancer 13.1.5 Gene families involved in carcinogenesis 13.1.6 Tumor suppressor or antioncogene genes 13.1.7 Oncogenic viruses 13.2 Molecular aspects of human herpesvirus 8 and associated tumors 13.2.1 Human herpesvirus 8 oncogenic viral genes and tumorigenesis 13.2.2 HHV-8-related diseases 13.3 Molecular aspects of human T-lymphotropic virus type 1 and associated tumors 13.3.1 HTLV-1 oncogenic viral genes and tumorigenesis 13.3.2 Diseases associated with HTLV-1 13.4 Conclusion References

227 228 229 229 229 230 231 232 233 233 235 235 236 237 237 238

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14. Hepatitis C virus and hepatocellular carcinoma

243

Pramodkumar Pyarelal Gupta, Viraj Jitendra Sadrani, Priyanshu Pramodkumar Gupta, Mala Makarand Parab and Virupaksha Ajit Bastikar 14.1 Introduction 14.1.1 The life cycle of the hepatitis C virus 14.2 The drug target of hepatitis C virus 14.3 Progression from hepatitis C virus to hepatocellular carcinoma 14.4 Hepatocellular carcinoma 14.5 Drugs and drug targets in hepatocellular carcinoma 14.6 Diagnosis of hepatitis C virus 14.7 Tests for liver damage 14.7.1 Hepatocellular carcinoma diagnosis and treatment 14.8 Conclusion References

15. Prostate cancer and viral infections: epidemiological and clinical indications

243 244 247 248 252 253 255 256 256 256 256

263

Berjas Abumsimir, Ihsan Almahasneh, Yassine Kasmi, Rahma Ait Hammou and Moulay Mustapha Ennaji 15.1 Introduction 15.2 Prostate cancer: clinical aspects 15.2.1 Prostate cancer detection, diagnosis, and staging 15.2.2 Prostate cancer epidemiology worldwide 15.3 Viral Infections as a risk factor for prostate cancer 15.3.1 Mouse mammary tumor virus 15.3.2 Human papillomavirus and prostate cancer References

16. Oncogenic human virus associated with prostate cancer: molecular epidemiology of Human Papillomavirus and Epstein-Barr virus

263 264 264 266 266 267 269 270

273

Dorine Florence Luthera Ngombe Mouabata, Gervillien Arnold Malonga, Ghislain Loubano-Voumbi, Patrina Joseph Iloukou Mayakia, Donatien Moukassa and Moulay Mustapha Ennaji 16.1 Introduction 16.1.1 History, taxonomy, and classification of human papillomavirus and Epstein-Barr virus 16.1.2 Molecular epidemiology of HPV and EBV associated with prostate cancer worldwide 16.1.3 Epidemiology of prostate cancer worldwide 16.1.4 Human papillomavirus and prostate cancer 16.1.5 Epstein-Barr virus

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16.1.6 Epidemiology of human papillomavirus and Epstein-Barr virus coinfection 16.1.7 Implications and associations between HPV and EBV prostate cancer 16.1.8 Coinfection with HPV and EBV 16.2 Conclusion References

17. Epidemiology of gynecological and mammary cancers in Africa: viral etiology and risk factors

xiii

280 281 282 284 284

289

Kawtar Aboulalaa, Chaymae Jroundi, Yassine Kasmi, Youssef Ennaji, Najwa Hassou, Imane Saif, Hlima Bessi, Longo Mbenza, Antoine Tshimpi, Bienvenu Lebwaze Massamba, Donatien Moukassa, Ange Antoine Abena, Etienne Mokondjimobe, Jean-Rosaire Ibara and Moulay Mustapha Ennaji 17.1 Introduction 17.2 Generalities about cancer 17.2.1 The definition of cancer 17.2.2 The origin of cancer cells 17.2.3 Carcinogenesis 17.2.4 Gynecological and mammary cancers 17.3 Epidemiology of gynecomammary cancers in Africa 17.3.1 Gynecomammary cancers in different continents 17.3.2 Gynecomammary cancer in Africa 17.3.3 Incidence and deaths linked to gynecomammary cancers in North Africa 17.3.4 Incidence and mortality rates of gynecomammary cancers in North Africa 17.4 Overview of the molecular oncogenesis of gynecomammary cancer 17.5 Oncoviruses associated with gynecomammary cancer 17.5.1 Human papillomavirus 17.5.2 Human mammary tumor virus 17.5.3 Epstein-Barr virus 17.5.4 Adenoviruses 17.5.5 Human polyomaviruses Acknowledgments References

18. Involvement of BK polyomavirus in genitourinary cancers

289 291 291 291 292 292 294 294 294 295 296 296 302 302 303 303 303 304 306 306

311

Ikram Tiabi, Mohammed Nabil Benchekroun and Moulay Mustapha Ennaji 18.1 Introduction

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18.2 The Polyomaviridae family 18.2.1 History of discovery 18.3 BK polyomavirus 18.3.1 Epidemiology 18.3.2 Modes of transmission 18.3.3 Virological characteristics 18.3.4 Structure of the viral particle 18.3.5 The viral capsid 18.3.6 Genomic organization of BK polyomavirus 18.3.7 Risk factors 18.4 Involvement of BK in genitourinary cancer 18.4.1 The prostate 18.4.2 The bladder 18.5 The kidney 18.6 Conclusion Acknowledgments References

19. Kidney cancer associated with Epstein-Barr virus

312 312 313 313 314 314 315 315 316 318 319 319 319 320 320 320 320 325

Meryem Sadkaoui, Ikram Tiabi, Youssef Ennaji, Nadia Takati, Najoie Filali-Ansari and Moulay Mustapha Ennaji 19.1 Introduction 19.2 Epstein-Barr virus 19.2.1 Morphology 19.3 The association between kidney cancer and Epstein-Barr virus 19.4 Conclusion Acknowledgments References Further reading

20. The involvement of human papillomavirus in breast cancer in general and the different prognostic biomarkers in triple-negative breast cancer

325 326 326 330 331 331 331 333

335

Soukayna Alaoui Sosse, Youssef Ennaji, Ikram Tiabi, Mohammed El Mzibri, Abdelilah Laraqui, Moussa koita and Moulay Mustapha Ennaji 20.1 20.2 20.3 20.4

Introduction Anatomy of the mammary gland Epidemiology Human papillomavirus 20.4.1 Route of human papillomavirus infection 20.4.2 Association between human papillomavirus infection and breast cancer 20.5 Triple-negative breast cancer

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Contents

20.5.1 Epidemiology 20.5.2 TP53 gene, p53 protein, and Ki-67 20.5.3 Epidermal growth factor receptor, c-KIT, and cytokeratins (CK 5/6, CK 14, CK 17, CK 56) 20.5.4 Vascular endothelial growth factor 20.5.5 Androgen receptor 20.6 Conclusion Acknowledgments References

21. Hypermethylation of tumor suppressor genes associated with Helicobacter pylori and Epstein
Barr virus infections in gastric cancer

xv 344 345 348 349 349 351 352 352

359

Fatima Ezzahra Rihane, Driss Erguibi, Farid Chehab and Moulay Mustapha Ennaji 21.1 Introduction 21.2 DNA methylation in gastric carcinogenesis 21.3 Helicobacter pylori and Epstein
Barr virus inducing aberrant methylation in the promoter of tumor suppressor genes 21.3.1 Helicobacter pylori inducing aberrant methylation in the promoter of tumor suppressor genes 21.3.2 Helicobacter pylori inducing aberrant methylation in the promoter of tumor suppressor genes via chronic inflammation 21.3.3 Epstein
Barr virus inducing aberrant methylation in the promoter of tumor suppressor genes 21.4 Helicobacter pylori coinfection with Epstein
Barr virus inducing aberrant methylation 21.5 Conclusion References

22. Etiology of human papillomavirus in cervical cancer and infection mechanism

359 360

361 361

362 363 366 366 366

373

Abderrahim Hatib, Rihabe Boussettine, Najwa Hassou and Moulay Mustapha Ennaji 22.1 22.2 22.3 22.4

Introduction Human papillomavirus cervical cancer risk factors Viral etiology of cervical cancer Biology of papillomavirus 22.4.1 Structural and genomic organization of human papillomavirus 22.4.2 Viral Infection and expression of viral oncoproteins 22.5 Interaction between E6 and p53 in the cancer pathway 22.5.1 P53 and cell cycle control

373 374 374 375 375 376 378 378

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22.6 Consequences of the E6 and p53 interaction 22.7 Interaction between E7 and pRb in the cancer pathway 22.8 Assessment of the joint action of oncoproteins E6 and E7 22.9 Vaccination is a way to fight against cervical cancer 22.10 Conclusion References

379 380 381 382 383 384

23. In vivo gene therapy with p53 or p21 adenovirus for prostate cancer

387

Rihabe Boussettine, Youssef Ennaji, Najwa Hassou, Hlima Bessi and Moulay Mustapha Ennaji 23.1 Introduction 23.2 Protein P53 23.2.1 History 23.2.2 P53 a gatekeeper 23.2.3 Structure of the P53 protein 23.2.4 Regulation of P53 23.2.5 Cellular localization 23.2.6 The functions of P53 23.3 Cell cycle arrest 23.3.1 Cell cycle arrest in the G1 phase 23.3.2 Cell cycle arrest in the G2 phase 23.4 Protein P21 23.4.1 P21 and cancer 23.5 Adenovirus 23.5.1 Nomenclature 23.5.2 Structure of adenovirus 23.5.3 Attachment and entry of the virus into the host cell 23.5.4 Early gene transcription 23.5.5 Genome replication 23.6 In vivo gene therapy with P53 or P21 adenovirus for prostate cancer 23.7 Conclusion References Index

387 388 388 389 390 391 393 393 394 394 394 395 395 397 397 398 398 399 405 405 407 407 417

List of contributors Ange Antoine Abena School of Health, Marien Ngouabi University, Brazzaville, Republic of the Congo Kawtar Aboulalaa Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Berjas Abumsimir Department of Medical Laboratory Sciences, Pharmacological & Diagnostic Research Centre (PDRC), Faculty of Allied Medical Sciences, AlAhliyya Amman University (AAU), Amman, Jordan; Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco; Pharmacological and Diagnostic Research Centre (PDRC), Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University (AAU), Amman, Jordan Sheik S.S.J. Ahmed Multi-omics and Drug Discovery Lab, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chennai, Tamil Nadu, India Ihsan Almahasneh Department of Applied Biology, College of sciences, University of Sharjah, Sharjah, United Arab Emirates Sembiyaa Arumugam Human Cytogenetics and Genomics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI) Chettinad Academy of Research and Education (CARE), Kelambakkam, Tamil Nadu, India Samira Zoa Assoumou Departement de Bacte´riologie-Virologie, Universite´ des Sciences de la Sante´ de Libreville, Gabon; Laboratoire Professeur Daniel Gahouma, Libreville, Gabon; Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Abdou Azzaque Institut de Recherche en Sciences de la Sante´ (IRSS/CNRST), Burkina, Faso Ragunath Barath Human Cytogenetics and Genomics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI) Chettinad Academy of Research and Education (CARE), Kelambakkam, Tamil Nadu, India

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List of contributors

Virupaksha Ajit Bastikar Amity Institute of Biotechnology, Amity University Mumbai, Maharashtra, India Hanaaˆ Bazir Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Mohammed Nabil Benchekroun Laboratory of Biotechnology, Environment and Health, Faculty of Science and Technology, University Hassan II-Mohammedia, Mohammedia, Morocco; Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Hlima Bessi Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco; Team of Ecotoxicology and Toxicology, Laboratory of Virology, Oncology, Biosciences, Environment and new Energies, Faculty of Sciences and Techniques, Mohammedia, University Hassan II of Casablanca, Morocco (LVO BEEN) Anicet Boumba Universite´ Marien Ngouabi, Pointe Noire, Congo Rihabe Boussettine Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Farid Chehab Service of Digestive Cancers Surgery and Liver Transplant, Department of Surgery, Ibn Rochd University Hospital Center, Faculty of Medicine & Pharmacy Casablanca, University Hassan II of Casablanca, Casablanca, Morocco Mohammed El Mzibri Plant Biotechnology Laboratory, Centre National de l’Energiedes Sciences et des Techniques Nucle´aires, Unite´ de Biologie Recherches Me´dicales-Division Sciences du Vivant, Rabat, Morocco; Life Sciences Division CNESTEN, Rabat, Morocco Moulay Mustapha Ennaji Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Youssef Ennaji Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco

List of contributors

xix

Driss Erguibi Service of Digestive Cancers Surgery and Liver Transplant, Department of Surgery, Ibn Rochd University Hospital Center, Faculty of Medicine & Pharmacy Casablanca, University Hassan II of Casablanca, Casablanca, Morocco Najoie Filali-Ansari Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Pramodkumar Pyarelal Gupta School of Biotechnology and Bioinformatics, D Y Patil Deemed to be University, Navi Mumbai, Maharashtra, India Priyanshu Pramodkumar Gupta Seven Star Pathology Lab, Mira Road East, Thane, Maharashtra, India Rahma Ait Hammou Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Najwa Hassou Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Abderrahim Hatib Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Jean-Rosaire Ibara School of Health, Marien Ngouabi University, Brazzaville, Republic of the Congo Chaymae Jroundi Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Yassine Kasmi Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Moussa koita Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco

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List of contributors

Arnaud Kombe Kombe Department of Obstetrics and Gynecology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, P. R. China Abdelilah Laraqui Research and Biosafety Laboratory, Mohammed V Military Teaching Hospital, Laboratory of Human Pathologies Biology, Faculty of Sciences, and Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco; Bio-Path Laboratory, Faculty of Sciences–Agadl, Mohammed V University, Rabat, Morocco Ghislain Loubano-Voumbi Faculty of Health Sciences, Marien Ngouabi University, Brazzaville, Republic of the Congo Gervillien Arnold Malonga Faculty of Health Sciences, Marien Ngouabi University, Brazzaville, Republic of the Congo Bienvenu Lebwaze Massamba School of Health, Marien Ngouabi University, Brazzaville, Republic of the Congo Patrina Joseph Iloukou Mayakia Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco; Faculty of Health Sciences, Marien Ngouabi University, Brazzaville, Republic of the Congo Longo Mbenza School of Medicine, University of Kinshasa, Kinshasa, Democratic Republic of the Congo Etienne Mokondjimobe School of Health, Marien Ngouabi University, Brazzaville, Republic of the Congo Donatien Moukassa School of Health, Marien Ngouabi University, Brazzaville, Republic of the Congo; Faculty of Health Sciences, Marien Ngouabi University, Brazzaville, Republic of the Congo Said Abdallah Nabil Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Dorine Florence Luthera Ngombe Mouabata Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco; Faculty of Health Sciences, Marien Ngouabi University, Brazzaville, Republic of the Congo Mala Makarand Parab School of Biotechnology and Bioinformatics, D Y Patil Deemed to be University, Navi Mumbai, Maharashtra, India

List of contributors

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Ragive Takale Parode Faculty of Health Sciences, Marien Ngouabi University, Brazzaville, Republic of the Congo Keerthana Raja Human Cytogenetics and Genomics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI) Chettinad Academy of Research and Education (CARE), Kelambakkam, Tamil Nadu, India B. Ranjith Human Cytogenetics and Genomics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI) Chettinad Academy of Research and Education (CARE), Kelambakkam, Tamil Nadu, India Fatima Ezzahra Rihane Laboratory of Genetic and Molecular Pathology, Faculty of Medicine & Pharmacy Casablanca, University Hassan II of Casablanca, Casablanca, Morocco; Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Meryem Sadkaoui Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Viraj Jitendra Sadrani Seven Star Pathology Lab, Mira Road East, Thane, Maharashtra, India Imane Saif Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco S. Sandeep Human Cytogenetics and Genomics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI) Chettinad Academy of Research and Education (CARE), Kelambakkam, Tamil Nadu, India Soukayna Alaoui Sosse Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco Tiatou Souhou Universite´ de Kara, Togo Nadia Takati Ecole Normale Supe´rieure Casablanca, Universite´ Hassan II de Casablanca, Casablanca, Morocco Ikram Tiabi Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco

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Antoine Tshimpi School of Medicine, University of Kinshasa, Kinshasa, Democratic Republic of the Congo Kaviarasan Vaishak Human Cytogenetics and Genomics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI) Chettinad Academy of Research and Education (CARE), Kelambakkam, Tamil Nadu, India Ramakrishnan Veerabathiran Human Cytogenetics and Genomics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI) Chettinad Academy of Research and Education (CARE), Kelambakkam, Tamil Nadu, India

About the editor Prof. Dr. Moulay Mustapha Ennaji is a scientist specialized in the fields of virology, hygiene, and microbiology. His educational qualifications include a Master of Science in 1986 and a PhD in virology in 1993—both from Armand Frappier Institute, University of Quebec (Canada)—and, a postdoctorate between 1991 and 1993—at the Canadian Red Cross. Additionally, he has been a research associate (1993
95) and a research officer (1995
96) at the National Council of Research of Canada; a visiting researcher at the University of California, Irvine, the United States; an abroad lecturer at the Histochemistry Institutes of Paris, France; and a guest researcher of the Franklin Foundation in USA NIH Bethesda. Dr. Ennaji has been a faculty in the Faculty of Sciences and Techniques Mohammedia (1996
97), falling under University Hassan II of Casablanca (UH2C); a lecturer and enabled professor (1997
2000) and the head of the biology department; and, is currently a professor of higher education in the same institution. A scientist concerned about the research development, Dr. Ennaji has been attending numerous conferences and giving lectures on virology, cancerology, hygiene, and microbiology since 1986 at many Moroccan, Canadian, and American universities. Dr. Ennaji had been the director (2005 and 2010) of virology, hygiene, and microbiology and a coordinator of the Consortium of Biomedical and Environmental Sciences Laboratories at UH2C-FSTM. Responsible for the master programs in biotechnology and biomedical technologies (2000
03), DESA of microbiology and bioengineering (2005
10), and master of science and technology (formally, MST Microbiology, Applied Virology, and Bioindustry Engineering and MST of Livings), he has also been at the helm of affairs at immuno-virology and applied microbiology from 2010 to 2015. Between 2005 and 2010, he was deputy head (2005
10) of the UFR DESA Biomedical Sciences and deputy leader (2000
05) of the UFR PhD in health and environment. Dr. Ennaji is deputy head (2005 to present) of Life and Environment Sciences Doctoral UFR. From 2010 to present, he has been the national expert at CNRST and a member of the National Commission for

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About the editor

scholarships. He was also a UNESCO expert (2012
14) on governance reform of university systems. Since 2008, he is a member of the Council of the Center of Doctoral Studies (CEDoc) at FSTM-UH2C. As the director (from 2010 to 2016) of the Laboratory of Virology, Microbiology, Quality, Biotechnologies/Ecotoxicology and Biodiversity at University Hassan II of Casablanca, Morocco, Dr. Ennaji had officiated as the leader of Virology, Oncology, Total Quality, and Medical Biotechnology Team, and Deputy Director of the Research Center of Natural Resources and Food (rensa) of UH2C. At present, as the director (From 2010 to 2024) of the Laboratory of Virology, Oncology, Biosciences, Environment and New Energies at the University Hassan II of Casablanca, Morocco, Dr. Ennaji is the leader of Virology Oncology and Biotechnology Team, and Deputy Director of the Research Center of Health and Biotechnologies of UH2C. Throughout his career, he has been rewarded with 24 awards, has organized numerous national and international meetings in the fields of virology, microbiology, and hygiene, and, at present, is the Vice President of the Moroccan Association of Biosafety, Cancer and Microbiology. Dr. Ennaji identifies himself as a Moroccan and Canadian citizen and native of Marrakesh (Morocco).

Preface The book, Oncogenic Viruses consists of two volumes: Volume 1: Fundamental of oncoviruses; and Volume II: Medical applications of viral oncology research. Volume I concerns the fundamentals of oncovirology. As completing the knowledge on the oncogenic virus, Volume II surfaced as the applied topics of oncology. With its theme of applied virology approaches, Volume II concerned medical treatments related to various human tumors suspected to be initiated by oncogenic viruses. The topics in Volume I cover mostly viral implications in humans; provide the most recent advanced tools and techniques in molecular oncovirology; discuss the computational methods and means of modeling viruses; create awareness about the manifestation of new transmissible oncogenic viruses; and highlight the need to adopt shared policies for the prevention and control of oncoviruses. In addition, Volume I will prove helpful to researchers in oncovirology, micromolecular virology, and medical virological sciences. Volume II, titled “Medical applications of viral oncology research,” is organized into a number of chapters, where each chapter includes definitions and key concepts as well as a wide description of the subject. An abstract giving a snapshot of what the chapter contains to begin with, the discussion in each chapter is supported by schematic figures and tables that are indispensable. Volume I begins with the editor giving a general introduction to the knowledge of oncogenic viruses, starting from past successes in discerning the nature of these viruses and explaining up to recent knowledge. Then he moves into introducing the importance of this specialized domain and flags the scope of future studies and how such studies can have an impact on human health. Since cancer—with its complexities and difficulties in understanding its nature even now—poses a scientific dilemma in which its causes are puzzling and therapy not always predictable, that makes it a challenge for science to call the small steps taken in its stride as achievements. Topics covered in Volume I are viral biomarkers, virus actions, vaccines, antiviral activities, bioinformatics, biology modeling, and epidemiology, besides covering human tumors such as lymphomas, prostate tumors, gynecomammary cancers, genitourinary cancers, cervical cancers, solid tumors, gastrointestinal cancers, which are some of the cancer types described.

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The main focuses of the chapters of Volume II concern the subjects of hepatocellular carcinoma associated with hepatitis B virus, general principles and mechanisms of viral oncogenic and associated cancers (cytomegalovirus, papilloma viruses, RNA oncogenic virus). In addition to the molecular diagnosis of human papilloma virus (HPV), the implications of HPV’s various strains in most cervical cancers are demystified. Coinfection of HPV and mouse mammary tumor virus, oncovirus in breast cancer tissues in women, the study of the inactivating effect exerted by oncovirus on tumor suppressor genes, MicroRNAs associated with Helicobacter pylori and Epstein-Barr virus (EBV) infections in gastric cancer comprise rest of the book. Besides, allied applied subjects on oncogenic human viruses covered here are associated with prostate cancer: molecular epidemiology of HPV and EBV, HPV and cervical cancer; the role of water as vectors of oncoviruses; and other subjects that enrich the repertoire of applied knowledge on oncogenic viruses. I hope we have covered the main applied oncovirology domains that will impact the quality of life of coming generations and may help humanity in its struggle against cancer. Moulay Mustapha Ennaji

Acknowledgments If the only prayer you say in your whole life is thank you, that will be enough. Maıˆtre Eckhart

Giving life to this newborn Oncogenic Viruses: Volume 1, Fundamentals of Oncoviruses, like all accouchements, has not been an easy thing, and it makes to call a crew of various colors in order to achieve a successful birth. In the same sense, this work would not have been possible without the participation of a distinguished group of eminent and prominent scientists, clinicians, and academicians in the medical world. In this context, I would like to address my sincere thanks to all the authors for their time and valuable contribution through the progress of the chapters, which present recent research news on the scientific and clinical aspects that affect oncoviruses. Special thanks are due to the reviewers—the invisible soldiers—who have contributed significantly to the improvement of the chapters’ contents to ensure the novelty of contents and guarantee the scientific quality based on their scientific expertise. We would also like to thank Elsevier and all their staff, who have contributed significantly to the publication of this book project at the right time and conditions. I would also like to thank the members of the editorial board who have invested a significant amount of time through the different stages of the publication of this book. Moulay Mustapha Ennaji

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Chapter 1

General introduction oncogenic viruses: recent knowledge Moulay Mustapha Ennaji Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco

Considerable research into the tumorigenesis factors have confirmed that the oncogenic viruses are a serious cause of some cancers and having a suspected role in other neoplastic growths. This field is full of arguments and controversial conclusions. Even related to one virus, there are different study designs and statements, such as population studied, former clinical and pathological criteria, other viruses implicated, and social status of probands studied. These differences and contradictory conclusions can be seen in the literature, but there is general agreement about the serious suspected roles of viruses in the initiation and development of cancer. One of the most famous oncogenic viruses, human papilloma virus (HPV), is responsible for major cervical cancers, especially in developing countries. HPV 16 and HPV 18 contribute toward malignancy and are classified as highrisk genital types with 70% of all cases in comparison to other HPV types and 20% of the adult population in Western countries (Faridi et al., 2011). In terms of relationships between oncogenic viruses and other tumors, approximately 4% of human T-lymphotropic virus type (HTLV-1)-infected individuals develop adult T cell leukemia/lymphoma (ATLL). HTLV-1 clinically causes two major diseases: ATLL and tropical spastic paraparesis/ HTLV-1-associated myelopathy. This virus is the first retrovirus that has been associated with human diseases, including an aggressive leukemia derived from CD41 T cells, according to Satou et al. (2011). Another virus that is associated with lymphoma is Epstein-Barr virus (EBV), and many studies have linked it to human immunodeficiency virus (HIV). This relationship is repeated between HIV and development of nonHodgkin’s lymphoma (NHL), as HIV-infected patients with profound immunodeficiency, are at substantial risk of developing NHL and particularly Oncogenic Viruses Volume 1. DOI: https://doi.org/10.1016/B978-0-12-824152-3.00005-6 Copyright © 2023 Elsevier Inc. All rights reserved.

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primary central nervous system lymphoma (Pluda et al., 1993). A positive association between hepatitis C virus (HCV) and risk of NHL has also been suggested (Matsuo et al., 2004). Other studies have reported different prevalence attribution of these types of lymphoma with HCV (Negri et al., 2004), but HCV prevalence in patients with B cell NHL (B-NHL) is approximately 15%, higher than that reported in general population (1.5%), suggesting a role of HCV in the etiology of BNHL. It is important to note that some clinical and pathological features of NHL are associated with HCV infection, but the virus does not seem to affect prognosis. In addition, a positive association between hepatitis B virus (HBV) infection and B-NHL raises the possibility that HBV may play an oncogenic role in the initiation of B-NHL (Gisbert et al., 2003; Keegan et al., 2005; Marcucci et al., 2006; Vallisa et al., 1999). According to the World Health Organization (WHO) the regions with the highest risk of HPV are Eastern Africa, Melanesia, and southern and central Africa. Unless cervical cancer prevention and control measures are successfully implemented, it is estimated that by 2030, approximately 800,000 new cases of cervical cancer will be diagnosed annually. The vast majority of these cases will be in developing countries. Since 2009, the WHO has recommended the inclusion of HPV vaccination in national immunization programs in countries where cervical cancer is a public health priority and where cost-effective and sustainable implementation of the vaccine is feasible (WHO, 2020). Since late 2019 the world has suffered from a unique pandemic situation caused by SARS-CoV-2, a zoonotic coronavirus that is the cause of COVID19. This disease leaves its effect on human health even after healing, and new symptoms are being revealed continually. This pandemic situation has alarmed the scientific community because of the serious effects of the viral infections on health and has emphasized the importance of an effective vaccination process. Neutralizing antibodies are crucial for vaccine-mediated protection against viral diseases. They probably act by blunting the infection, which is then resolved by cellular immunity. The protective effects of neutralizing antibodies can be achieved by neutralization of free virus particles and by several activities that are directed against infected cells. Several viruses have evolved mechanisms to evade neutralizing antibody responses, and these viruses present special challenges for vaccine design that are now being tackled (Burton, 2002). There are two immune systems. Most organisms possess innate immunity, and vertebrates also have the adaptive system, which is necessary for developing vaccines. The former involves cells such as dendritic cells and macrophages, which also have important roles in the adaptive system. The latter is characterized by lymphocytes, which possess specific receptors that recognize foreign antigens (Gordon, 2007).

General introduction oncogenic viruses: recent knowledge Chapter | 1

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Vaccine approaches to infectious diseases are widely applied and appreciated. Among them, vectors based on recombinant viruses have shown great promise and play an important role in the development of new vaccines. The ideal viral vector should be safe and enable efficient presentation of required pathogen-specific antigens to the immune system (Souza et al., 2005). Scientists know the importance of vaccination for minimizing the chances of developing cancer. Vaccine therapy for cancer is less toxic than chemotherapy or radiation and therefore could be especially effective in older, more frail cancer patients. However, it has been shown that older individuals do not respond to vaccine therapy as well as younger adults do (Gravekamp, 2009). In this book we focus also on the importance of vaccinations against viruses for cancer patients. Based on current evidence, including clinical and epidemiological studies of various tumors, and because of the similarity with the same serosity of oncoviruses mechanism of action, it might be that the findings will be accumulated, realizing a confirmed oncogenic viruses’ role in the initiation and progression of such tumors. In addition, the underlying tumorigenesis mechanisms in the vast majority of human cancers could be accurately identified. For the reason, it is possible to recommend HPV vaccines or developing other vaccines for other oncogenic viruses to avoid further human tumors, improving the lives of many people. This book is dedicated to providing an update on the molecular biology of oncogenic viruses and recent findings. It is presented in two volumes. Volume 1, Fundamental of Oncovirus, provides basic knowledge about fundamental of oncogenic viruses. Volume 2, Medical Applications of Oncology Knowledge, discusses the oncogenic viruses in relation to the threat of human cancers.

References Burton, D. A. (2002). Viruses and vaccines. Nature Reviews Immunology, 2, 706
713. Faridi, R., Zahra, A., Khan, K., et al. (2011). Oncogenic potential of Human Papillomavirus (HPV) and its relation with cervical cancer. Virology Journal, 8, 269. Available from https://doi.org/10.1186/1743-422X-8-269. Gisbert, J. P., Garc´ıa-Buey, L., Pajares, J. M., & Moreno-Otero, R. (2003). Prevalence of hepatitis C virus infection in B-cell non-Hodgkin’s lymphoma: Systematic review and metaanalysis. Gastroenterology, 125(6), 1723
1732. Gordon, A. (2007). The importance of vaccination. Frontiers in Bioscience, 12, 1278
1290. Gravekamp, C. (2009). The importance of the age factor in cancer vaccination at older age. Cancer Immunology, Immunotherapy, 58, 1969. World Health Organization (2020). Guide to introducing HPV vaccine into national immunization programmes 2020. Available from: www.who.org. (Retrieved on 12 September 2020). Keegan, T. H., Glaser, S. L., Clarke, C. A., Gulley, M. L., Craig, F. E., DiGiuseppe, J. A., . . . Ambinder, R. F. (2005). Epstein-Barr virus as a marker of survival after Hodgkin’s lymphoma: A population-based study. Journal of Clinical Oncology, 23(30), 7604
7613.

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Marcucci, F., Mele, A., Spada, E., Candido, A., Bianco, E., Pulsoni, A., . . . De Renzo, A. (2006). High prevalence of hepatitis B virus infection in B-cell non-Hodgkin’s lymphoma. Haematologica, 91(4), 554
557. Matsuo, K., Kusano, A., Sugumar, A., Nakamura, S., Tajima, K., & Mueller, N. E. (2004). Effect of hepatitis C virus infection on the risk of non-Hodgkin’s lymphoma: A meta-analysis of epidemiological studies. Cancer Science, 95(9), 745
752. Pluda, J. M., Venzon, D. J., Tosato, G., Lietzau, J., Wyvill, K., Nelson, D. L., . . . Yarchoan, R. (1993). Parameters affecting the development of non-Hodgkin’s lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy. Journal of Clinical Oncology, 11(6), 1099
1107. Satou, Y., Yasunaga, J. I., Zhao, T., Yoshida, M., Miyazato, P., Takai, K., . . . Yamaguchi, T. (2011). HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. PLOS Pathogens, 7(2), e1001274. Souza, A. P. D., et al. (2005). Recombinant viruses as vaccines against viral diseases. Brazilian Journal of Medical and Biological Research, 38, 509
522. Vallisa, D., Berte`, R., Rocca, A., Civardi, G., Giangregorio, F., Ferrari, B., . . . Cavanna, L. (1999). Association between hepatitis C virus and non-Hodgkin’s lymphoma, and effects of viral infection on histologic subtype and clinical course. The American Journal of Medicine, 106(5), 556
560.

Chapter 2

Hepatocellular carcinoma associated with hepatitis B virus and environmental factors Hanaaˆ Bazir1, Hlima Bessi2, Mohammed Nabil Benchekroun1 and Moulay Mustapha Ennaji1 1

Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco, 2Team of Ecotoxicology and Toxicology , Laboratory of Virology, Oncology, Biosciences, Environment and new Energies, Faculty of Sciences and Techniques, Mohammedia, University Hassan II of Casablanca, Morocco (LVO BEEN)

2.1

Introduction

Hepatocellular carcinoma (HCC) is a malignant tumor of the liver that develops from hepatocytes. It is the most common primary malignant tumor of the liver, followed by cholangiocarcinoma, which develops from cells of the bile ducts. HCC is one of the leading causes of cancer death worldwide. HCC has a geographic distribution that overlaps that of hepatitis B, with increased frequency in sub-Saharan Africa and Asia, particularly China. However, the risk factors for HCC are changing, and this geographic distribution is fading. With the near-universal use of vaccination against the hepatitis B virus (HBV) and drugs to control the replication of the virus, the number of cases of HCC due to hepatitis B is decreasing. A decrease in the number of cases of HCC due to chronic hepatitis C has been observed, resulting from the discovery of drug combinations that are very effective in eliminating the hepatitis C virus (HCV) in affected patients. On the other hand, there has been an increase in the number of cases of HCC linked to overweight and diabetes. Obesity and type 2 diabetes mellitus are conditions that substantially increase the risk of developing HCC (Lange & Dufour, 2019).

Oncogenic Viruses Volume 1. DOI: https://doi.org/10.1016/B978-0-12-824152-3.00020-2 Copyright © 2023 Elsevier Inc. All rights reserved.

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2.2 2.2.1

Hepatocellular carcinoma Epidemiology and etiological factors

2.2.1.1 Incidence Primary liver cancer is the seventh most common cancer and the fourth leading cause of cancer deaths worldwide (Bray et al., 2015). While we have seen a decrease in the incidence and impact of many other cancers, the global burden of primary liver cancer worldwide has increased in recent decades (El-Serag, 2012; Tang et al., 2018). HCC represents more than 90% of primary liver cancers, and in nearly 90% of cases, it develops in the context of chronic liver disease, most often in the stage of cirrhosis (Singal et al., 2020). The etiology of the underlying disease is known in about 90% of cases. Worldwide, these are mainly infections with HBV or HCV and less frequently from excessive alcohol consumption and/or unrelated steatotic liver disease alcohol (Singal et al., 2020). Exposure to hepatocarcinogenic toxins is also a significant risk factor in some parts of the world. For example, over 90% of the general population in several West African countries is exposed to aflatoxins as a result of improper postharvest processing, while exposure is minimal in Western countries (Hamid et al., 2013). The incidence and the main etiological factors involved in hepatocarcinogenesis are shown in Fig. 2.1. The highest incidence of HCC is observed in East Asia, with Mongolia having the highest incidence of HCC in the world. HBV is the main causative factor in most parts of Asia (except Japan), South America, and Africa; HCV is the main causative factor in Western Europe, North America, and Japan, and alcohol consumption is the causative factor in Central and Eastern Europe. Nonalcoholic steatohepatitis (NASH), the main etiology included in the “Other” category is a rapidly increasing risk

FIGURE 2.1 The incidence of HCC by geographic area and etiology. HCC, hepatocellular carcinoma.

Hepatocellular carcinoma associated with hepatitis B virus Chapter | 2 Females

Males Eastern Asia Micronesia Southeastern Asia Northern Africa World Melanesia Polynesia Western Africa Southern Europe Northern America Australia and New Zealand Middle Africa Western Europe Central America Caribbean Northern Europe Central and Eastern Europe Southern Africa Eastern Africa Western Asia South America South-Central Asia

26.9 24.2 21.2 20.2

8.9 5.3 7.1 10.5 5.2 9.0 4.2 5.6 3.2 3.7 2.9 3.7 2.6 5.7 4.3 3.2 2.6 3.0 3.9 3.3 3.3 2.0

14.1 13.8 11.6 11.4 10.5 10.1 9.5 8.7 8.6 6.9 6.8 6.8 6.7 6.6 6.2 6.2 5.5 4.0

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10

7

0

10

20

30

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ASR (World) per 100 000

FIGURE 2.2 Age-standardized (world) incidence rates, liver, by sex.

factor that is expected to become the predominant cause of HCC in income regions in the near future (Sung et al., 2021) (Figs. 2.1 and 2.2). An increase in the incidence of HCC is expected until 2030, when it is possible that a decrease will be observed as a result of the efforts that have been made in recent decades to fight against infections by HBV and HCV, in particular with the generalization of vaccination against HBV and the development of antiviral treatments (Valery et al., 2018). However, the prospect of an increase in the prevalence of obesity and its metabolic complications, such as diabetes, and the increase in per capita alcohol consumption in some regions of the world could lead to an increased risk of HCC, which potentially could offset the decrease in the proportion linked to viral hepatitis (Valery et al., 2018). Overall, the prognosis for individuals with HCC is grim, with 5-year survival rates of around 10% (Bray, et al., 2015) (Fig. 2.2).

2.2.2

Mortality

As with the incidence, large variations in overall mortality are observed around the world, reflecting the large disparities in access to screening programs and specific treatments for cancer, regardless of the etiology (Figs. 2.3 and 2.4) (Bray et al., 2018). It is estimated that around 85% of HCC cases occur in low- or medium-resource areas, particularly in East Asia and subSaharan Africa (Figs. 2.3 and 2.4).

2.3

Anatomopathological characteristics

The macroscopic aspects of HCC are extremely variable; in particular, it can range in size from a few millimeters to more than 20 cm in diameter. It is a malignant hepatocyte epithelial tumor (Roncalli, 2004).

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Mortality t8.2 5.3–8.2 4.3–5.3 3.1–4.3 70 years (n=96)

Age (years) FIGURE 18.3 Seroprevalence of BK virus by age (Kean et al., 2009).

BKPyV s is a virus that infects humans from childhood (Fig. 18.3). In children aged 1
5 years, the seroprevalence is approximately 38%, while in children aged 5
10 years, the seroprevalence is almost the same as that of adults, that is, 74.6% (Kean et al., 2009). These results are consistent with primary infection occurring at an early age.

18.3.2 Modes of transmission The oropharyngeal route is the most likely route of entry of the virus into the body because of the very early age of seroconversion (65%
90% seropositive before 10 years of age) and the detection of viral DNA in saliva and lymphoid tissues of the oropharyngeal area (Jeffers et al., 2009). A second possible route of entry is ingestion of contaminated food or water. BKPyV is found in the environment (Bofill-Mas et al., 2000). Other modes of transmission of the virus are possible but have been rarely described. Detection of the viral genome in lymphocytes of blood donors is an indication of possible transmission by blood (Dolei et al., 2000).

18.3.3 Virological characteristics Human polyomavirus type 1 (HPyV1), better known as BKPyV, is, like all other members of this family, a small, nonenveloped virus. It is approximately

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FIGURE 18.4 BKPyV purified by light microscopy (Panou et al., 2018). BKPyV, BK polyomavirus.

45 nm in diameter (Tognon et al., 2003), with a circular double-stranded DNA molecule as the genome (Fig. 18.4).

18.3.4 Structure of the viral particle The genome of BKPyV contains about 5200 bp. In the viral cell the circular DNA is associated with cellular histones H2A, H2B, H3, and H4, creating a minichromosome structure. Its capsid is icosahedral and is composed of the association of VP1 particles, called major proteins, with VP2 and VP3 proteins, called minor proteins. This capsid is made up of 360 VP1 molecules arranged in 72 pentamers, which give it its icosahedral shape. The Cterminal part of a VP1 molecule associates with the neighboring VP1 molecule to close the pentamer. Each VP1 pentamer is associated with a VP2 or VP3 protein that is located at its center. Thus only the VP1 protein is in contact with the outside, as shown in Fig. 18.5.

18.3.5 The viral capsid As with all polyomaviruses, BKPyV is a naked icosahedral capsid virus. It consists of 72 capsomeres, as can be demonstrated by electron microscopy (Fig. 18.6). A capsomere consists of the combination of a pentamer of the major capsid protein VP1 associated with one of the two minor capsid proteins VP2 or VP3 (Fig. 18.5). Although this capsid association is pentameric, the triangulation number is T 5 7 with the pentamers occupied by hexameric spaces. The viral particle has a diameter of 45 nm (Takemoto & Mullarkey, 1973).

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FIGURE 18.5 Representation of the structure of BKPyV (Helle et al., 2017). BKPyV, BK polyomavirus.

FIGURE 18.6 BKPyV particles are observed in a urine sample by electron microscopy (magnification: 152,000 3 and 800,000 3 ) (Hirsch & Steiger, 2003). BKPyV, BK polyomavirus.

18.3.6 Genomic organization of BK polyomavirus Like other polyomaviruses, BK virus is composed of a double-stranded DNA of approximately 5000 bp, enveloped in an icosahedral capsule (De Gascun & Carr, 2013; Jiang et al., 2009). Its genome has three regions: G

The early region, which includes the transcribed part of the genome, with two regulatory proteins, T antigen and t antigen.

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G

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The late region, which codes for the capsid proteins VP1 (the main protein), VP2, and VP3. The noncoding regulatory region, which is located between the early and late regions. It does not contain DNA polymerase in its machinery, which means that it uses infected cells for replication of its DNA (Fig. 18.7).

The first step of the infection consists of the binding of VP1 to the receptors of the infecting cell at the polysialylated gangliosides of the membrane surface. This is followed by a phase of internalization by endocytosis and then transport to the cytosol through the endoplasmic reticulum, probably via the microtubule pathway (Bennett et al., 2015). Next, the viral genome is delivered into the nucleus for replication through the use of VP2 and VP3 and the import pathway involving the nuclear pores of importins α/β1 (Low et al., 2004). The viral genome is then transcribed in the nucleus by using the cellular machinery of DNA. The viral proteins VP1, VP2, and VP3 are converted in the cytoplasm and then imported into the nucleus, and new viral molecules are formed. New virions are thought to appear in the nucleus of the host cell about 48 hours after infection (Corneille & Boutolleau, 2011) (Fig. 18.8). 1. The cycle begins with the attachment of virus particles to ganglioside receptors and/or N-glycoproteins that contain α(2,8)-sialic acid on the surface of permissive cells. 2. The virus is internalized after caveolae-mediated endocytosis, 4 hours after adsorption. 3. The virus crosses the late endosomes and enters the endoplasmic reticulum (ER) about 10 hours after infection. 4. In the ER the virus is already partially decapsidated by the action of chaperone proteins, isomerases, and reductases. This leads to the creation of a hydrophobic surface by the identification of VP2 and VP3, which

NCCR ORI

Agnoprotein VP2

Early

tAg

VP3

BKV genome

Truncated TAg

VP1

TAg

FIGURE 18.7 Genome structure of BK polyomavirus (De Gascun & Carr, 2013).

Late

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1. Link between VP1 and GT1b / GD1b 2. Caveosome

Endoplasmic reticulum

4. Partial uncoating

3. Microtubules traffiking

5. Retrotranslocation Low Ca++ 6. Uncoating

Host RNA polymerase II

Nuclear pore Viral DNA

VP1

7. Viral replication

Rb family p53 8. Cell cycle activation Apoptosis inhibition

FIGURE 18.8 The BK polyomavirus multiplication cycle. BK polyomavirus remains one of the most common viral infections after kidney disease (Helle et al., 2017).

5.

6. 7. 8. 9.

10. 11.

will integrate with the ER membrane and thus allow the release of the partially decapsidized particle into the cytosol with the involvement of the cytosol with the involvement of the protein degradation machinery. The viral genome is then transported into the nucleus through the nuclear pore by the NLS carried by VP2/VP3 and the importin α/β1 pathway. Early gene expression occurs about 24 hours after infection. The early proteins are translocated into the nucleus, where they initiate replication of the viral genomic DNA. The late genes are expressed. VP1, VP2, and VP3 are introduced into the nucleus, where they aggregate to form capsids into which newly synthesized viral DNA molecules are integrated. The viral progeny is diffused by infectious cells after cell lysis. However, some of the virions could be diffused into the extracellular medium by a nonlytic pathway, depending on the cellular secretion pathway.

18.3.7 Risk factors Risk factors for BK virus are poorly identified, especially in children. Nevertheless, seronegativity of the recipient for BK virus with the graft of a

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seropositive recipient appears to be a risk factor for the development of BK virus nephropathy (Smith et al., 2004). However, depending on the center, the patient’s status is not always assessed before transplantation (Bohl et al., 2005). BK virus nephropathy also appears to be more common in male recipients and in recipients of transplants performed from living donors (Prince et al., 2009). Donor-recipient HLA incompatibility is a risk factor for BK virus nephropathy, related to the fact that it encourages graft rejection and the dissemination of inflammatory factors that provide a fertile ground for the development of BK virus (Awadalla et al., 2004). One study showed that lack of HLA C7 was a risk for prolonged viremia. This makes it likely that this allele plays a role in cellular immune protection against BK virus (Bohl et al., 2005) through antigen presentation or natural killer cell activation.

18.4 Involvement of BK in genitourinary cancer 18.4.1 The prostate Prostate cancer (PCa) is the third largest cause of death and the fourth most important cause of cancer death in Western countries (Jemal et al., 2011). It is becoming increasingly important worldwide as a consequence of increasing life expectancy and the development of diagnostic techniques (Choudhury et al., 2012; Hayes & Barry, 2014). The pathogenesis of this malignancy, which has other consistent risk factors (Ahmed et al., 2014; Allott et al., 2013), is due to chronic inflammatory states, and proliferative inflammatory atrophy (PIA) is assumed to be the key transitional stage to overt PCa (De Marzo et al., 1999). Infectious agents are considered to be important inflammatory factors for the occurrence of PCa (Sfanos & De Marzo, 2012). This includes viruses (Das et al., 2008), which appear to play an important role in the development of PIA. However, the involvement of viruses in prostate carcinogenesis remains to be demonstrated (Delviks-Frankenberry et al., 2012). Human polyomavirus BK (BKV) is a circular double-stranded DNA virus that belongs to the Polyomaviridae family (Johne et al., 2011). It causes a permanent, persistent and asymptomatic infection in the urinary tract, residing latently in the urothelia (Hirsch et al., 2003).

18.4.2 The bladder The relationship between bladder cancer and BKV is based on the binding and inactivation of p53 and pRB proteins by viral proteins. Monini et al. reported that BKV was the main culprit in 58% of bladder cancer cases (Monini et al., 1995).

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18.5 The kidney Researchers have come to different findings about the role of BKV in kidney cancers. of Narayanan et al. found BKV DNA in a poorly differentiated renal cell carcinoma that developed on a transplanted kidney and was present in a metastatic lymph node, which suggested a role for the virus in the development of the tumor. The tumor did not contain any other virus, and the nontumor tissue was free of viral particles, as were the other four renal tumors studied as controls (Narayanan et al., 2007) However, in the epidemiological study of Newton (Newton et al., 2005), there was no difference in the level of anti-BKV antibodies in plasma collected before diagnosis in prostate cancer cases.

18.6 Conclusion BKPyV is a ubiquitous virus that affects more than 80% of the adult population. Although it is asymptomatic in immunocompetent individuals, it can cause hemorrhagic cystitis in hematopoietic stem cell transplant recipients or interstitial nephropathy after renal transplantation.

Acknowledgments The authors would like to thank the Minister of National Education, Professional Training, Higher Education and Scientific Research, and many thanks to members of the Virology, Oncology and Medical Biotechnology team at FSTM-Hassan II University of Casablanca for all their efforts to support us during all work stages on this research.

References Abend, J. R., Jiang, M., & Imperiale, M. J. (2009). BK virus and human cancer: Innocent until proven guilty, . Seminars in cancer biology (Vol. 19, pp. 252
260). Academic Press, No. 4. Ahmed, A., Ali, S., & Sarkar, F. H. (2014). Advances in androgen receptor targeted therapy for prostate cancer. Journal of Cellular Physiology, 229(3), 271
276. Allott, E. H., Masko, E. M., & Freedland, S. J. (2013). Obesity and prostate cancer: Weighing the evidence. European Urology, 63(5), 800
809. Awadalla, Y., Randhawa, P., Ruppert, K., Zeevi, A., & Duquesnoy, R. J. (2004). HLA mismatching increases the risk of BK virus nephropathy in renal transplant recipients. American Journal of Transplantation, 4(10), 1691
1696. Bennett, S. M., Zhao, L., Bosard, C., & Imperiale, M. J. (2015). Role of a nuclear localization signal on the minor capsid proteins VP2 and VP3 in BKPyV nuclear entry. Virology, 474, 110
116. Bofill-Mas, S., Pina, S., & Girones, R. (2000). Documenting the epidemiologic patterns of polyomaviruses in human populations by studying their presence in urban sewage. Applied and Environmental Microbiology, 66(1), 238
245. Bohl, D. L., Storch, G. A., Ryschkewitsch, C., Gaudreault-Keener, M., Schnitzler, M. A., Major, E. O., & Brennan, D. C. (2005). Donor origin of BK virus in renal transplantation and role

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of HLA C7 in susceptibility to sustained BK viremia. American Journal of Transplantation, 5(9), 2213
2221. Carbone, M., Pass, H. I., Miele, L., & Bocchetta, M. (2003). New developments about the association of SV40 with human mesothelioma. Oncogene, 22(33), 5173
5180. Choudhury, A. D., Eeles, R., Freedland, S. J., Isaacs, W. B., Pomerantz, M. M., Schalken, J. A., . . . Visakorpi, T. (2012). The role of genetic markers in the management of prostate cancer. European Urology, 62(4), 577
587. Corneille, J., & Boutolleau, D. (2011). Infections a` virus BK apre`s allogreffe de cellules souches he´matopoı¨e´tiques. Virologie, 15(2), 115
125. Dalianis, T., & Hirsch, H. H. (2013). Human polyomaviruses in disease and cancer. Virology, 437(2), 63
72. Das, D., Wojno, K., & Imperiale, M. J. (2008). BK virus as a cofactor in the etiology of prostate cancer in its early stages. Journal of Virology, 82(6), 2705
2714. De Gascun, C. F., & Carr, M. J. (2013). Human polyomavirus reactivation: Disease pathogenesis and treatment approaches. Clinical and Developmental Immunology, 2013, 373579. Delviks-Frankenberry, K., Cingo¨z, O., Coffin, J. M., & Pathak, V. K. (2012). Recombinant origin, contamination, and de-discovery of XMRV. Current Opinion in Virology, 2(4), 499
507. De Marzo, A. M., Marchi, V. L., Epstein, J. I., & Nelson, W. G. (1999). Proliferative inflammatory atrophy of the prostate: Implications for prostatic carcinogenesis. The American Journal of Pathology, 155(6), 1985
1992. Dolcetti, R., Martini, F., Quaia, M., Gloghini, A., Vignocchi, B., Cariati, R., . . . Tognon, M. (2003). Simian virus 40 sequences in human lymphoblastoid B-cell lines. Journal of Virology, 77(2), 1595
1597. Dolei, A., Pietropaolo, V., Gomes, E., Di Taranto, C., Ziccheddu, M., Spanu, M. A., . . . Degener, A. M. (2000). Polyomavirus persistence in lymphocytes: Prevalence in lymphocytes from blood donors and healthy personnel of a blood transfusion centre. Journal of General Virology, 81(8), 1967
1973. Gosert, R., Rinaldo, C. H., Funk, G. A., Egli, A., Ramos, E., Drachenberg, C. B., & Hirsch, H. H. (2008). Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology. The Journal of Experimental Medicine, 205(4), 841
852. Gross, L. (1953). A filterable agent, recovered from AK leukemic extracts, causing salivary gland carcinomas in C3H mice. Proceedings of the Society for Experimental Biology and Medicine, 83(2), 414
421. Hayes, J. H., & Barry, M. J. (2014). Screening for prostate cancer with the prostate-specific antigen test: A review of current evidence. JAMA: The Journal of the American Medical Association, 311(11), 1143
1149. Helle, F., Brochot, E., Handala, L., Martin, E., Castelain, S., Francois, C., & Duverlie, G. (2017). Biology of the BKPyV: An update. Viruses, 9(11), 327. Helle, F., Brochot, E., Handala, L., Martin, E., Castelain, S., Francois, C., & Duverlie, G. (2017). Biology of the BKPyV: an update. Viruses, 9(11), 327. Hirsch, H. H., & Steiger, J. (2003). Polyomavirus BK. The Lancet Infectious Diseases, 3(10), 611
623. Hirsch, F. R., Varella-Garcia, M., Bunn., Di Maria., Veve, R., Bremnes, R. M., & Franklin, W. A. (2003). Epidermal growth factor receptor in non
small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. Journal of clinical oncology, 21(20), 3798
3807.

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Jeffers, L. K., Madden, V., & Webster-Cyriaque, J. (2009). BK virus has tropism for human salivary gland cells in vitro: Implications for transmission. Virology, 394(2), 183
193. Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., & Forman, D. (2011). Global cancer statistics. CA: A Cancer Journal for Clinicians, 61(2), 69
90. Jiang, M., Abend, J. R., Tsai, B., & Imperiale, M. J. (2009). Early events during BK virus entry and disassembly. Journal of Virology, 83(3), 1350
1358. Johne, R., Buck, C. B., Allander, T., Atwood, W. J., Garcea, R. L., Imperiale, M. J., . . . Norkin, L. C. (2011). Taxonomical developments in the family Polyomaviridae. Archives of Virology, 156(9), 1627
1634. Kean, J. M., Rao, S., Wang, M., & Garcea, R. L. (2009). Seroepidemiology of human polymaviruses. PLoS Patholgens, 5(3)e1000363. Low, J., Humes, H. D., Szczypka, M., & Imperiale, M. (2004). BKV and SV40 infection of human kidney tubular epithelial cells in vitro. Virology, 323(2), 182
188. Macsween, K. F. (2003). DH Crawford Avance´es re´centes du virus Epstein-Barr. The Lancet Infectious Diseases, 3, 131
140. Matsuoka, M. (2003). Human T-cell leukemia virus type I and adult T-cell leukemia. Oncogene, 22(33), 5131
5140. Monini, P., Rotola, A., Di Luca, D., De Lellis, L. A. U. R. A., Chiari, E., Corallini, A., & Cassai, E. (1995). DNA rearrangements impairing BK virus productive infection in urinary tract tumors. Virology, 214(1), 273
279. Narayanan, M., Szymanski, J., Slavcheva, E., Rao, A., Kelly, A., Jones, K., & Jaffers, G. (2007). BK virus associated renal cell carcinoma: Case presentation with optimized PCR and other diagnostic tests. American Journal of Transplantation, 7(6), 1666
1671. Newton, R., Ribeiro, T., Casabonne, D., Alvarez, E., Touze´, A., Key, T., & Coursaget, P. (2005). Antibodies against BK virus and cancers of the prostate, kidney and bladder in the EPIC-Oxford cohort. British Journal of Cancer, 93, 1305
1306. Panou, M. M., Prescott, E. L., Hurdiss, D. L., Swinscoe, G., Hollinshead, M., Caller, L. G., & Macdonald, A. (2018). Agnoprotein is an essential egress factor during BK polyomavirus infection. International Journal of Molecular Sciences, 19(3), 902. Prince, O., Savic, S., Dickenmann, M., Steiger, J., Bubendorf, L., & Mihatsch, M. J. (2009). Risk factors for polyoma virus nephropathy. Nephrology Dialysis Transplantation, 24(3), 1024
1033. Schowalter, R. M., Pastrana, D. V., Pumphrey, K. A., Moyer, A. L., & Buck, C. B. (2010). Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host & Microbe, 7(6), 509
515. Sfanos, K. S., & De Marzo, A. M. (2012). Prostate cancer and inflammation: The evidence. Histopathology, 60(1), 199
215. Smith, J. M., McDonald, R. A., Finn, L. S., Healey, P. J., Davis, C. L., & Limaye, A. P. (2004). Polyomavirus nephropathy in pediatric kidney transplant recipients. American Journal of Transplantation, 4(12), 2109
2117. Spencer, S., Feltkamp, M. C., Daugherty, M. D., Moens, U., Ramqvist, T., Johne, R., & Ehlers, B. (2016). A taxonomy update for the family Polyomaviridae. Archives of Virology, 161(6), 1739
1750. Takemoto, K. K., & Mullarkey, M. F. (1973). Human papovavirus, BK strain: Biological studies including antigenic relationship to simian virus 40. Journal of Virology, 12(3), 625
631. Thoulouzan, M., Courtade-Saidi, M., Kamar, N., Bellec, L., Huyghe, E., Soulie´, M., & Plante, P. (2010). Aspects urologiques de l’infection a` Polyomavirus. Progre`s en Urologie, 20(1), 11
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5200. Van Regenmortel, M. H. V., Mayo, M. A., Fauquet, C. M., & Maniloff, J. (2000). Virus nomenclature: Consensus vs chaos. Archives of Virology, 145(10), 2227
2232. zur Hausen, H. (2000). Papillomavirus causant le cancer: E´vasion du controˆle de la cellule hoˆte dans les premiers e´ve´nements de la carcinogene`se. Journal of the National Cancer Institute, 92, 690
698.

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Chapter 19

Kidney cancer associated with Epstein-Barr virus Meryem Sadkaoui1, Ikram Tiabi1, Youssef Ennaji1, Nadia Takati2, Najoie Filali-Ansari1 and Moulay Mustapha Ennaji1 1

Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco, 2Ecole Normale Supe´rieure Casablanca, Universite´ Hassan II de Casablanca, Casablanca, Morocco

19.1 Introduction Renal cell carcinoma or kidney cancer is the most common solid lesion of the kidney, accounting for about 90% of all malignant kidney tumors. There are risk factors that increase the risk for cancer, including smoking, hypertension, obesity, and others related to the environment. During the discovery of Epstein-Barr virus (EBV) and the first studies in 1950 in Uganda, the Denis Burkitt observed and described tumors in certain children. These included tumors of the upper jaw but also of different organs, such as the kidneys, liver, stomach and ovaries, thyroid, and heart. EBV is the cause of a chromosomal abnormality presenting translocations that cause the myc oncogene (chromosome 8) to pass under the control of Ig promoters of chromosomes 14, 2, or 22 (translocations 8:14; 8:2; and 8:22) (Faculte´ de Me´decine Pierre et Marie Curie Universite´ Pierre et Marie, Curie; 2016
2017). Acute renal failure is a major public health problem in all developed countries, and developing countries are not exempt from it, considering the increases in pathologies such as diabetes, hypertension, and cardiovascular diseases (Failal et al., 2020). The management of this pathology has undergone significant progress, particularly the improvement of extrarenal purification techniques with its different modalities; however, the mortality remains high due to the evolution of the characteristics of the population of patients in acute renal failure such as older age, the coexistence of chronic pathologies (hypertension, diabetes, heart disease, neoplasia, etc.), multiple mechanisms, and the discovery of AKI at late stages (Failal et al., 2020). Oncogenic Viruses Volume 1. DOI: https://doi.org/10.1016/B978-0-12-824152-3.00001-9 Copyright © 2023 Elsevier Inc. All rights reserved.

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19.2 Epstein-Barr virus 19.2.1 Morphology The structure of EBV is generally similar to that of the herpesviruses. From the inside out, it consists of a nucleoid, a capsid, a tegument, and an envelope. The nucleoid is composed of a double-stranded linear DNA, wrapped around a protein structure. Formed by 162 capsomers, the icosahedral capsid that covers the nucleoid is itself surrounded by an asymmetric fibrillar structure: the integument. Finally, the envelope, coming from nuclear or intracytoplasmic membranes or intracytoplasmic membranes, has on its surface about ten viral glycoproteins in the form of spicules (Larrat, 2010) (Figs. 19.1).

19.2.1.1 The Epstein-Barr virus family With a broad spectrum, EBV has the capacity to infect various hosts, including mammals, fish, and birds. This virus belongs to the herpesvirus type, and the human herpesvirus belongs to the Herpesviridae family. Their distribution is into three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae; these consist of eight human herpesviruses. Their infection capacity is high, and the virus can remain in the latency phase in reservoir cells. Belonging to the

ENVELOPE

NUCLEOID

VIRAL ANTIGENS

CAPSID

FIGURE 19.1 Structure of the Epstein-Barr virus.

CAPSOMERES

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Human Herpesvirus 8 KSHV

Alloherpesviridae Alphaherpesvirinae

Rhadinovirus Percavirus

Herpesvirales

Herpesviridae

Gammaherpesvirinae Macavirus

Betaherpesvirinae

Lymphocryptovirus

Malacoherpesviridae Order

Family

Sub-family

Genus

Species Human Herpesvirus 4 EBV

FIGURE 19.2 Classification of Epstein-Barr virus (EBV).

Gammaherpesvirinae subfamily and the genus Lymphocryptovirus, EBV exhibits this persistence of infection (Fig. 19.2).

19.2.1.2 Transmission mode The chief mode of transmission in vivo is through saliva, which subsequently allows EBV to diffuse into the oropharyngeal sphere. There is a possibility of transmission through organ grafting, during blood transfusion, and between mother and child during childbirth or in breastfeeding. 19.2.1.3 Risk factors When classified according to importance, the chief risk factors for EBV is chronic renal failure (atrophic and cystic small kidneys), with a sevenfold increase in the risk of papillary tumor. There are three other risk factors: smoking, obesity, and high blood pressure. However, in these cases the significance is limited, without disregarding the heritable factor. The heritable transmissible conditions that predispose to renal tumors include von Hippel-Lindau (VHL) disease, which is accompanied by carcinomas that are characterized by multiple clear cells, early and intermittent, which aggravate the complaint. Other rare conditions include heritable papillary carcinoma and Birt-Hogg-Dube´ syndrome (UMVF, 2014) In terms of genetic conditions, we find that these conditions are due to the transmission of certain genes with abnormalities. For example, 75% of cases of VHL disease are due to the transmission of the relevant gene on chromosome 3, and the MET proto-oncogene has been connected to familial forms of papillary carcinoma. The risk of kidney cancer increases in patients with end-stage renal disease; kidney transplant patients, who may be more likely to have cancer in the native kidney than in the transplanted kidney; and patients with high

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blood pressure. Cohort studies are mounting. That the risk of kidney cancer increases with the rise in blood pressure leads us to believe that excess body weight may have a relationship with kidney cancer. Studies that have been done in the United States and in France show this connection to more than 40% and more than 30% of cases of kidney cancer, respectively. The risk of developing this type of cancer increases with increasing body mass. Other hormonal factors may increase the risk of kidney cancer. A Canadian study showed that risk of kidney cancer may increase in multiparous women compared with nulliparous women by 40%
90%. The relationship may be with the use of contraception or treatment acting on the hormonal level; however, this has not been demonstrated. The environmental risk factors are tobacco and diet. Tobacco use, taking into consideration the duration and the number of cigarettes smoked, can increase the risk of developing kidney cancer. Nevertheless, a diet that is rich in vegetables and fruits decreases the risk and plays a protective role. Many study have shown that the consumption of antioxidants, including polyphenols (Erdem et al., 2012), beta-carotene, vitamins, and nutrients, is inversely proportional to the risk of developing kidney cancer.

19.2.1.4 Viral structure The EBV virion can be divided into five parts from the inside out. First is an icosahedral capsid of approximately 150 nm, which contains the genome of the virus of 172 kb (line B95
8) and codes for approximately 85 proteins. Then we have the capsid, which is itself surrounded by an integument, which contains proteins, virals, and at the end a lipid bilayer whose composition of the glycoproteins of the virus (Fig. 19.3). Glycoprotein envelope

150 nm DNA

Tegument

Capsid Lipid envelope

FIGURE 19.3 The viral structure of Epstein-Barr virus (produced by Dr Ge´oui Thibault (2006)) and electron microscopy image of EBV. EBV, Epstein-Barr virus. Adapted from Young, L.S., and Rickinson, A.B. (2004). Epstein-Barr virus: 40 years on. Nature Reviews. Cancer 4, 757
768.

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19.2.1.5 Genomic organization The EBV genome was cloned from Escherichia coli in 1980 (Dambaugh et al., 1980) and was fully sequenced from the B95.8 strain in 1984 (Baer et al., 1984). This is a core virus strain derived from marmoset B cells infected with an EBV virus strain that was isolated from humans during primary infection (Miller et al., 1972). The genome in the virus particle is a linear double-stranded DNA of approximately 172 kb, flanked at both ends by two terminal repeat sequences and composed of 60% guanine and cytosine (Dambaugh et al., 1980). During cellular infection the EBV genome circularizes on the basis of its terminal repeat sequences to form an episome covalently closed circle (Adams & Lindahl, 1975), which can bind tightly to host cell chromatin but does not integrate into the cellular genome. 19.2.1.6 Viral replication EBV, like all human viruses, must infect a human cell in order to replicate. It then relies on the cellular machinery to initiate and maintain the production of new infecting virions (Adams & Lindahl, 1975). 19.2.1.7 Target cells As with all Herpesviridae, EBV infection starts with the penetration of the virus into a cell. In the case of EBV, this occurs in the epithelial cells of the oropharynx. Although seroprevalence is very high, the primary infection is asymptomatic the majority of the time. Sometimes, in the case of adolescents or young adults, it can lead to NMI. During primary infection the patient is contagious. Viral particles are produced and widely released in salivary secretions. The virus then persists throughout life in a latent state in the B lymphocytes of memory with probable reactivations (Fig. 19.4). Reactivation

Virus entry

Infection

Proliferation

Differentiation

Persistence

Buccal cavity Oropharyngeal mucosa

Lymph Node Germinal center

FIGURE 19.4 Epstein-Barr virus infection (Heslop, 2009).

Peripheral Circulation

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consists of a restart of the lytic cycle, leading to the production of new infecting virions (Li, et al., 2007). The current model of EBV infection is based on the hypothesis that B lymphocytes located in the oropharyngeal epithelium are the main cells infected by EBV. The formation of a complex between four glycoproteins (gH, gL, gB, gp110, and gp42) is essential for the entry of EBV into the cell and in particular for the fusion of the cell and viral envelopes. In this process, the complex allows gp42 to interact with the human leukocyte antigen (HLA) class II molecule, leading to the appearance of EBV (Li et al., 2007) and then endocytosis of the virus. The penetration of EBV into epithelial cells involves a more complicated mechanism, which is not yet fully understood. Epithelial cells show only very low expression of CD21 in vitro, and it is completely absent in vivo. In addition, the level of expression of HLA class II molecules is very low, which makes the presence of gp42 essential for virus penetration. EBV attachment and entry would require interaction between the glycoproteins gH and gL on a particular receptor gHgLR (Fig. 9) (Wang et al., 1998). Another hypothesis is that epithelial cell infection results from direct communication between an infectious B lymphocyte and an epithelial cell. In this case, the epithelial cell would be more sensitized to the infection of a virus that was already attached to a B cell but not internalized.

19.3 The association between kidney cancer and EpsteinBarr virus In France, according to Public Health France, the number of incident cases of kidney cancer in 2015 was estimated to be 8885 cases for men and 4397 cases for women, a total of 13,282 cases in 2015 with a male-to-female ratio of 2 (Leone et al., 2015). In 2017, Public Health France estimated 14,150 new cases per year. This increase has been seen since 1980. Indeed, the standardized rate of kidney cancer has increased by 2% per year in men and 1.7% per year in women from 1980 to 2012. According to Public Health France, kidney cancer is the third most common cancer of the urogenital system in adults, after prostate and bladder cancer. It accounts for 3% of adult solid cancers and is the sixth leading cause of cancer death in industrialized countries (Charles et al., 2010). The average age at diagnosis is 67 years for men and 70 years for women (Belot et al., 2008). There have been a few reports of renal pathologies associated with EBV infection. The diagnosis of EBV infection was based mainly on positive serology. In the case of patients with renal disease despite repeated negative serologies, molecular hybridization techniques, namely, in situ hybridization (ISH) and polymerase chain reaction (PCR), showed that they were infected with EBV. Site-specific molecular probes directed to specific EBV genomic regions and repeated in tandem were used. A synthetic 23-mer biotin-

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terminally labeled oligonucleotide probe from the NotI region of EBV was used for ISH. For PCR, oligonucleotide primers were designed from sequences of the highly conserved internal long direct repeat region of EBV to specifically amplify a 110-base pair segment. The first patient, a 3-yearold girl with a 1-year history of fatigue, fever, splenomegaly (Nadasdy et al., 1992), and lymphadenopathy, developed hematuria. A renal biopsy revealed extensive glomerular mesangiolysis mixed with segmental mesangial sclerosis; no immunological deposits were noted by electron microscopy or immunofluorescence. ISH on resected spleen and lymph node sections was positive for EBV. The second patient, a 28-year-old male renal allograft recipient, was treated with a double dose of OKT3. Seven weeks after transplantation, a kidney biopsy revealed a lymphoproliferative disorder. Kerosene sections of the nephrectomy specimen were positive for EBV by both ISH and PCR. It is clear that EBV cannot be excluded on the basis of multiple negative serologies in some patients, and ISH and PCR can lead to the detection of viral genomic information in renal and nonrenal tissues (Nadasdy et al., 1992).

19.4 Conclusion Chronic kidney disease is a major public health problem in terms of severity, silence, difficulty, and cost. It is characterized by the progressive and permanent reduction of glomerular filtration rate (GFR). This decrease in GFR is the result of the decrease in the number of functional nephrons. The insidious nature of chronic kidney disease makes it a formidable disease. In addition, it is asymptomatic in the initial stages of the disease, and its diagnosis can be only biological.

Acknowledgments The authors would like to thank the Minister of National Education, Professional Training, Higher Education and Scientific Research, and many thanks to members of the Virology, Oncology and Medical Biotechnology team at FSTM-Hassan II University of Casablanca for all their efforts to support us during all work stages on this research.

References Adams, A., & Lindahl, T. (1975). Epstein-Barr virus genomes with properties of circular DNA molecules in carrier cells. Proceedings of the National Academy of Sciences of the United States of America, 72, 1477
1481. Baer, R., Bankier, A. T., Biggin, M. D., Deininger, P. L., Farrell, P. J., Gibson, T. J., Hatfull, G., Hudson, G. S., Satchwell, S. C., & Se´guin, C. (1984). DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature, 310, 207
211.

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Belot, A., Grosclaude, P., Bossard, N., Jougla, E., Benhamou, E., Delafosse, P., et al. (2008). Cancer incidence and mortality in France over the period 1980
2005. Revue d’Epidemiologie et de Sante Publique, 56(3), 159
175. Charles, T., Lindner, V., Matau, A., Roy, C., & Lang, H. (2010). Cancer du rein. EMC Elsevier Masson SAS Paris Urol [Internet]. [cite´ 16 aouˆt 2017]; (18-096-A-10). Connolly, S. A., Jackson, J. O., Jardetzky, T. S., & Longnecker, R. (2011). Fusing structure and function: A structural view of the herpesvirus entry machinery. Nature Reviews. Microbiology, 9(5), 369
381. Available from https://doi.org/10.1038/nrmicro2548. Dambaugh, T., Beisel, C., Hummel, M., King, W., Fennewald, S., Cheung, A., Heller, M., RaabTraub, N., & Kieff, E. (1980). Epstein-Barr virus (B95-8) DNA VII: Molecular cloning and detailed mapping. Proceedings of the National Academy of Sciences of the United States of America, 77, 2999
3003. Epstein, M. A., Henle, G., Achong, B. G., & Barr, Y. M. (1965). Morphological and biological studies on a virus in cultured lymphoblasts from Burkitt’s lymphoma. The Journal of Experimental Medicine, 121, 761
770. Erdem, M. G., Cinkilic, N., Vatan, O., Yilmaz, D., Bagdas, D., & Bilaloglu, R. (2012). Genotoxic and anti-genotoxic effects of Vanillic Acid against mitomycin C-induced genomic damage in human lymphocytes in vitro. Asian Pacific Journal of Cancer Prevention, 13 (10), 4993
4998. Faculte´ de Me´decine Pierre et Marie Curie Universite´ Pierre et Marie Curie. Failal, I., Ezzaki, S., Mtioui, N., Elkhayat, S. S., Zamed, M., Medkouri, G., . . . . . . Ramdani, B. (2020). Insuffisance re´nale aigue¨: Profil e´pide´miologique, e´tiologique, the´rapeutique et e´volutif. Ne´phrologie & The´rapeutique, 16(5), 326. Heslop, H. E. (2009). How I treat EBV lymphoproliferation. Blood, 114(19), 4002
4008. Available from https://doi.org/10.1182/blood-2009-07-143545. Larrat, S. (2010). Inhibition du cycle lytique du Virus Epstein-Barr par ARN interfe´rence. Doctoral dissertation, Universite´ Joseph-Fourier-Grenoble I. Leone, N., Voirin, N., Roche, L., Binder-Foucard, F., Woronoff, A.-S., Delafosse, P., et al. (2015). Rapport technique. [cite´ 16 aouˆt 2017]. Li, X., Ghandri, N., Piancatelli, D., Adams, S., Chen, D., Robbins, F.-M., Wang, E., et al. (2007). Associations between HLA class I alleles and the prevalence of nasopharyngeal carcinoma (NPC) among tunisians. Journal of Translational Medicine, 5(May), 22. Available from https://doi.org/10.1186/1479-5876-5-22. Miller, G., Shope, T., Lisco, H., Stitt, D., & Lipman, M. (1972). Epstein-Barr virus: Transformation, cytopathic changes, and viral antigens in squirrel monkey and marmoset leukocytes. Proceedings of the National Academy of Sciences of the United States of America, 69, 383
387. Nadasdy, T., Park, C. S., Peiper, S. C., Wenzl, J. E., Oates, J., & Silva, F. G. (1992). EpsteinBarr virus infection-associated renal disease: Diagnostic use of molecular hybridization technology in patients with negative serology. Journal of the American Society of Nephrology: JASN, 2(12), 1734
1742. UMVF (2014). Universite´ Me´dicale Virtuelle Francophone. Wang, X., Kenyon, W. J., Li, Q., Mu¨llberg, J., & Hutt-Fletcher, L. M. (1998). Epstein-Barr virus uses different complexes of glycoproteins gH and gL to infect B Lymphocytes and epithelial cells. Journal of Virology, 72(7), 5552
5558. Young, L. S., & Rickinson, A. B. (2004). Epstein-Barr virus: 40 years on. Nature Reviews. Cancer, 4, 757
768.

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Further reading Bock, C. H., Ruterbusch, J. J., Holowatyj, A. N., Steck, S. E., Van Dyke, A. L., Ho, W. J., et al. (2018). Renal cell carcinoma risk associated with lower intake of micronutrients. Cancer Medicine, 7(8), 4087
4097. Chow, W.-H., Gridley, G., Fraumeni, J. F., Jr, & Ja¨rvholm, B. (2000). Obesity, hypertension, and the risk of kidney cancer in men. The New England Journal of Medicine, 343(18), 1305
1311. Cumberbatch, M. G., Rota, M., Catto, J. W. F., & La Vecchia, C. (2016). The role of tobacco smoke in bladder and kidney carcinogenesis: A comparison of exposures and meta-analysis of incidence and mortality risks. European Urology, 70(3), 458
466. David, T. P., Stobach, R. S., Ckane, M., & Davis, J. R. (1992). Biology 0; disease: Epstein-Barr virus associated lymphoproliferative disorders. Laboratory Investigation, 67(l). Epstein, M. A., Achong, B. G., & Barr, Y. M. (1964). Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet, 1(7335), 702
703. Gertrude, H., Werner, H., & Evelyne, T. L. (1979). The Epstein-Barr virus. Scientific American, 241(1), 40
51. ˇ Bo¨hmig, G. A., et al. (2010). Klatte, T., Seitz, C., Waldert, M., De Martino, M., Kikic, Z., Features and outcomes of renal cell carcinoma of native kidneys in renal transplant recipients. BJU International, 105(9), 1260
1265. Lambe, M., Lindblad, P., Wuu, J., Remler, R., & Hsieh, C. (2002). Pregnancy and risk of renal cell cancer: a population-based study in Sweden. British Journal of Cancer, 86(9), 1425
1429. Lee, J. E., Hankinson, S. E., & Cho, E. (2009). Reproductive factors and risk of renal cell cancer. American Journal of Epidemiology, 169(10), 1243
1250. Morand, P., & Seigneurin, J. M. (1989). Biologie du virus d’Epstein-Barr. Annales de Biologie Clinique (47), 421
427. Sante´ Publique France. Estimation nationale de l’incidence et de la mortalite´ par cancer en France entre 1980 et 2012/2013/Maladies chroniques et traumatismes/Rapports et synthe`ses/Publications et outils/Accueil [Internet]. [cite´ 23 juill 2018]. Strauss, J. H., & Strauss, E. G. (2002). Viruses and human disease (VII, p. 383). San Diego: Academic Press. Weikert, S., Boeing, H., Pischon, T., Weikert, C., Olsen, A., Tjonneland, A., et al. (2008). Blood pressure and risk of renal cell carcinoma in the european prospective investigation into cancer and nutrition. American Journal of Epidemiology, 167(4), 438
446.

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Chapter 20

The involvement of human papillomavirus in breast cancer in general and the different prognostic biomarkers in triplenegative breast cancer Soukayna Alaoui Sosse1, Youssef Ennaji1, Ikram Tiabi1, Mohammed El Mzibri2, Abdelilah Laraqui3,4, Moussa koita1 and Moulay Mustapha Ennaji1 1 Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco, 2Plant Biotechnology Laboratory, Centre National de l’Energiedes Sciences et des Techniques Nucle´aires, Unite´ de Biologie Recherches Me´dicales-Division Sciences du Vivant, Rabat, Morocco, 3Research and Biosafety Laboratory, Mohammed V Military Teaching Hospital, Laboratory of Human Pathologies Biology, Faculty of Sciences, and Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco, 4Bio-Path Laboratory, Faculty of Sciences–Agadl, Mohammed V University, Rabat, Morocco

20.1 Introduction Breast cancer is the most common cancer in women, with a total of 2.08 million new cases (11.6% of all new cases in women) in 2018 alone (Bray et al., 2018). Accounting for 15% of total cancer-related deaths, breast cancer is the leading cause of death in women worldwide (Bray et al., 2018). In Morocco, considering both sexes, breast cancer ranked first and accounted for 19.2% of cases, followed by lung cancer with 12.3% and colorectal cancer with 7.8% (Incidence, Mortality and Prevalence by cancer site. Globocan 2018). Breast cancer accounted for 20% of all diagnosed cancers in both sexes and 35.8% of cases in women. Almost all of the affected patients (91%) were female. Fewer than 1% of the recorded cases were in males (Benider et al., 2016). Several risk factors for the occurrence of breast cancer have been recognized, such as a family history of breast cancer, advanced age, early puberty, Oncogenic Viruses Volume 1. DOI: https://doi.org/10.1016/B978-0-12-824152-3.00004-4 Copyright © 2023 Elsevier Inc. All rights reserved.

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late menopause, nulliparity, and obesity, but no factor has been directly implicated in its occurrence except the inherited transmission of the BRCA1 and BRCA2 genes, which are involved in 5%
10% of breast cancer cases. Many viruses are suspected in the etiology of breast cancer (El Fouhi et al., 2020). It has been estimated that 20% of all human cancers have an infectious origin (Howley, 2006). Oncogenesis can be induced either directly by viral genes or by viruses that reduce host immunity. More than 40 different viruses have been identified by genome sequencing. However, only four of these viruses are suspected of having a potential oncogenic influence in breast cancer. These are mouse mammary tumor virus, human papillomavirus (HPV), Epstein-Barr virus (EBV), and bovine leukemia virus. Each of these four oncogenic viruses has been studied as a distinct infectious pathogen in benign breast tissue and subsequent breast cancer from the same patients. HPV and EBV are DNA viruses. The viral load of high-risk cancer HPVs is 2000 times lower in breast cancer than in cervical cancer. Although these viruses can be detected by wholegenome sequencing, amplification techniques such as nested polymerase chain reaction (PCR) may be required for successful identification. However, PCR results may be inconsistent or even falsely negative. It can also be argued that these viral loads are so low that they may not be oncogenic. Breast cancer mortality is often related to relapse and/or progression of disease that could not be permanently eradicated by treatment. It appears that relapse rates are higher in the case of so-called aggressive and/or poor prognosis cancers. These include young female breast cancer and triple-negative breast cancer (TNBC), both of which are known to have a poor prognosis with significant tumor aggressiveness and a higher risk of relapse (Bauer et al., 2007; Gajdos et al., 2000; Kroman et al., 2000; Li et al., 2017). In the case of young women, in addition to the usual consequences of treatment (alopecia, hematological toxicities, etc.), age-specific side effects may be observed. This is particularly true of chemically induced menopause, which affects only women of childbearing age and will have repercussions on the lives of these young women, particularly on their quality of life (Goodwin et al., 1999). TNBC is a highly studied subtype because of its aggressiveness and the absence of targeted therapies. Indeed, metastatic relapse is more frequent in this tumor subtype, and its heterogeneity represents a real challenge in oncology. This chapter has two parts. The first part focuses on the involvement of HPV in breast cancer in general; the second part discusses prognostic biomarkers in triple-negative breast cancer.

20.2 Anatomy of the mammary gland The breast is an organ made up mainly of fatty tissue that rests on the pectoral muscles with the help of ligaments called Cooper’s ligament. In women its main function is lactation, whereas in men, the breasts remain immature and have no role. The human mammary gland consists of a composite

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tubuloalveolar structure formed by 15
25 irregular lobes radiating from the nipple. The skin surrounding the nipple, the areola, is pigmented and contains sebaceous glands (Morgan’s glands) that enlarge during pregnancy and become known as Montgomery’s tubercle. The secretions of these glands probably contribute to protection of the nipple and areola during lactation. The lobes that form the mammary gland are separated by a layer of dense connective tissue and are embedded in fatty tissue. A single duct, the milk duct, drains each lobe through its own opening on the surface of the nipple. Just before opening to the surface, the milk duct forms a dilation called the lactiferous sinus. The nipple contains trabeculae of smooth muscle oriented parallel to the galactophores and circularly near its base. Within each lobe the main duct branches into numerous branches to form the terminal ducts, each leading to a lobule consisting of multiple acini or alveoli (Fig. 20.1).

20.3 Epidemiology Worldwide, approximately 2.1 million new cases of female breast cancer were diagnosed in 2018, accounting for nearly one in four cancer cases in women (Fig. 20.2).

FIGURE 20.1 Schematic representation of a sagittal breast section (by Patrick Lynch).

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Breast cancer incidence rates are highest in Australia/New Zealand, Northern Europe (e.g., the United Kingdom, Sweden, Finland, and Denmark), Western Europe (Belgium [with the highest global rates], the Netherlands, and France), Southern Europe (Italy), and North America (Fig. 20.3).

20.4 Human papillomavirus 20.4.1 Route of human papillomavirus infection Mucous membranes and skin are the most common sites of infection for various microorganisms (Pier, 2013), including HPV (Moody & Laimins, 2010). HPV infection occurs through tissue lesions, which are necessary to ensure that the virus has access to basal keratinocytes (Liu & Baleja, 2008). Once these cells are reached, L1 protein binds to heparin-sulfate proteoglycan (HSPG) (Greber, 2016), promoting a conformational change in the viral capsid (Buck et al., 2013). Although recognized as an important binding site, HSPG is not unique, as studies show that L1 protein can also bind to different integrins, such as integrin α6 (CD49f), 332 (laminin 5) (Florin et al., 2012), and α6β4 (Calinisan et al., 2012). Conformational changes in the capsid expose the Nterminal region of the L2 protein (Buck et al., 2013), which is cleaved by furin (Buck et al., 2013; Day & Schiller, 2009), a protein with proteolytic activity that is capable of interacting with various growth factors and cellular and viral receptors (Bassi et al., 2001). This action is necessary to promote a second conformational change of the viral capsid that allows the binding of the virus to cellular receptors, including integrin α6β4 (Buck et al., 2013; Day & Schiller, 2009). Next, the virus is internalized into vacuolar structures by clathrin- or caveolin-mediated endocytosis mechanisms (Day et al., 2003). When lysosomes bind to these endocytic vesicles, forming phagolysosomes, a pH reduction occurs, leading to the disassembly of the viral capsid and thus to the release of the viral genome (Day et al., 2003). However, HPV is not able to self-replicate, as the virus does not express polymerases. Therefore during the amplification process, early (E) proteins interact with the host cell, inducing entry into S phase as a mechanism for obtaining DNA polymerases (Moody & Laimins, 2010). However, this proliferative action can lead to DNA replication stress (Spardy et al., 2008) and consequently to numerical and structural chromosomal instability (Duensing et al., 2000; Duensing & Mu€nger, 2002), which can lead to cancer initiation. Viral assembly is verified in most differentiated epithelial layers (Munday, 2014). Virus release occurs during degeneration of differentiated cells (Brobst & Hinsman, 1966; Buck et al., 2013; Munday, 2014), resulting in the formation of koilocytes (Araldi et al., 2014; Bogaert et al., 2010). The term “koilocyte” comes from the Greek koillos (meaning “cavity”). This term was introduced by Koss and Durfee in 1956 to refer to a cytopathic alteration characterized by a prominent halo and pycnotic nucleus

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Incidence 18.1 million new cases 18.40%

29.30%

3.20%

6.60%

9.20% 8.20% 8.20%

3.30% 3.80% 4.50% 5.30% Lung

Colorectum.

Stomach

Liver

Breast

Esophagus

Panceas

Prostate

Cervix uteri

Leukemia

Others

FIGURE 20.2 Pie charts show the distribution of cases and deaths for the ten most common cancers in 2018 for (A) both sexes, (B) men, and (C) women. For each sex, the area of the pie chart reflects the proportion of total cases or deaths; nonmelanoma skin cancers are included in the “other” category (GLOBOCAN 2018).

FIGURE 20.3 Bar graph of age-standardized incidence and mortality rates by region for female breast cancer in 2018. Rates are presented in descending order of the global agestandardized rate (W), and the highest national age-standardized rates for incidence and mortality are overlaid (GLOBOCAN 2018).

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(Ferraro et al., 2011). Koilocytosis is considered a pathognomonic marker of papillomavirus infection [122,123]. The formation of koilocytosis is attributed to E5 and E6 oncoproteins, although the mechanism of vacuolation is still unclear (Krawczyk et al., 2008, 2010). However, one study suggests that cytoplasmic vacuolization contributes to keratinocyte fragility, thus facilitating virion relocation (Krawczyk et al., 2008). Thus koilocytes are cells that are destined for apoptosis (Krawczyk et al., 2008), which is a consequence of the inhibition of macromolecule synthesis (Wang & Kieff, 2013) (Fig. 20.4).

FIGURE 20.4 Schematic models showing HPV infection and viral pathology. (1A) HPV infects microinjured epithelial tissue. HPV, human papillomavirus. (1B) Among these proteins are the oncoproteins E5, E6 and E7. E5 binds to EGF, conferring mitogenic stimulation along with an anti-apoptotic stimulus through ubiquitination of Bax. The E6 oncoprotein cooperates with this anti-apoptotic stimulus by ubiquitinating p53, at the same time as binding to XRCC1. These actions increase mutational status, leading to genomic instability. The E7 oncoprotein cooperates in genomic instability, by reducing levels of histone γ-H2 AX, which is involved in DSB repair. E7 also promotes phosphorylation of pRb, contributing to cell proliferation. (1C) Persistent viral infection increases genomic instability and can lead to cancer initiation. After cancer initiation, viral oncoproteins promote metabolic deregulation, leading to EMT, increasing expression of mesenchymal markers (Araldi et al., 2018).

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20.4.2 Association between human papillomavirus infection and breast cancer Several authors have reported the infection of CB HPV in different populations around the world (Fig. 20.5). There are three main routes of transmission of HPV to breast tissue: (1) from the infected genital site to the breast via blood or other bodily fluid, (2) by direct contact between the genital site and the breast resulting from abnormal sexual activity, and (3) from the mouth to the breast as a result of to oral sexual activity (Fig. 20.6). The putative mechanism of HPV in breast carcinogenesis is shown in Fig. 20.7. Breast cancer cells show relatively high expression of ERα and low expression of ERβ. Both types of nuclear hormone receptors form homodimers or heterodimers upon ligand binding and translocate to the cell nucleus for transcriptional regulation, which is the primary function of ERs. ER

Country

Benign HPV%

China China USA Brazil Turkey Greece Korea China Japan Mexico Australia China Mexico Mexico China Italy Australia Iran China China Iraq Iran Iran China China

18/52, 34.6 14/32, 43.8 25/29, 86.2 25/101,24.7 37/50, 74.0 17/107, 15.9 8/123, 6.5 8/62, 12.9 26/124, 20.9 15/51, 29.4 1/26, 3.8 24/40, 60.0 3/67, 4.4 6/60, 10.0 4/62, 6.4 9/31, 29.0 25/50, 50.0 15/58, 25.8 48/224, 21.4 7/7, 100.0 60/129, 46.5 22/65, 33.8 10/55, 18.1 2/100, 2.0 25/169, 14.7

Breast tumor Malignant HPV 18 (%) 0/52, 0.0 0/24, 0.0 10/101, 9.9 20/50, 40.0 3/124, 2.4 3/51, 5.8 1/62, 1.6 4/79, 5.0 35/129, 27.1 1/55, 1.8 -

Adjacent normal breast HPV %

Tissue preservaon type

Methods of detecon

16/50, 32.0 0/31, 0.0 8/62, 12.9 0/11, 0.0 0/43, 0.0 1/20, 5.0 0/40, 0.0 7/60, 11.6 0/46, 0.0 0/12 8/40, 20.0 1/41, 2.4 6/37, 16.2 3/44, 6.8 0/65, 0.0 7/51, 13.7 0/50, 0.0 1/83, 1.2

PET PET PET PET CPT CPT PET CPT PET PET PET CPT PET PET CPT PET CPT PET Lump CPT PET PET PET CPT PET

PCR/Southern PCR/Southern PCR/In situ PCR/Seq PCR PCR PCR/Chip PCR/Southern PCR PCR PCR/In situ PCR PCR PCR PCR INNO-Lipa HPV PCR PCR/Seq HC2 HC/Seq In situ PCR\Seq PCR MS-PCR PCR

FIGURE 20.5 Worldwide prevalence of HPV in breast tumor and adjacent normal breast tissue (Araldi et al., 2018). HPV, human papillomavirus.

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FIGURE 20.6 Representative diagram showing the possible route of HPV transmission to breast tissue. HPV, human papillomavirus.

dimers bind to the ER region of target genes and recruit coregulators to achieve regulation of transcriptional activity. Another mechanism by which ERs control the expression of target genes is by acting as a coregulator for other transcription factors. Canonical Wnt signaling plays significant roles in many biological and pathological processes, such as breast and breast tumorigenesis. Wnt ligands bind to frizzled membrane receptors and LRPs, attenuating β-catenin ubiquitination by β-TrCP. Accumulation of β-catenin allows translocation into the nucleus and downstream transcriptional activation. Inhibitors of Wnt signaling, such as DKKs and SFRPs, function as tumor suppressors by contributing to β-catenin degradation, thereby preventing transcription of β-catenin-targeted oncogenes.

20.5 Triple-negative breast cancer TNBC, which is known for its aggressiveness and lack of specific therapies, is currently one of the most studied subtypes of breast cancer The classification of breast cancers into different molecular subtypes, which is used for patient management, is based primarily on hormone receptor expression and the ERBB2 (HER2/neu or the gene encoding the HER2 receptor) amplification status of the tumor TNBC is characterized by an absence of hormone receptor expression (estrogen and progesterone) and an absence of ERBB2 amplification. The

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FIGURE 20.7 Schematic diagram representing the putative mechanism of HPV in mammary carcinogenesis. (A) E6 interaction with E6-AP, leading to p53 degradation, resulting in increased cell proliferation and ultimately transformation into immortalized mammary epithelial cells (MECs). (B) E6 bound to human telomerase reverse transcriptase (hTERT) may mediate MEC immortalization through inactivation of the p14ARF-p53 pathway. (C) E6 could increase mammary cell proliferation through regulation of Cox2. This results from the degradation of NFX1 by E6, which results in downregulation of p105 and stabilizes NF-κβ, which can then activate COX2 transcription. (D) The interaction of E6/E7 with HER2 results in its activation. HER2 in turn activates c-Src, which leads to phosphorylation of beta-catenin at its C-terminus, resulting in translocation of beta-catenin to the nucleus and activation of various proliferation-associated genes. (E) E6/E7 inhibits BRCA1 function, resulting in restoration of estrogen receptor (ER) expression. Elevated ER expression leads to increased proliferation of breast cells due to modulation of various proliferation-associated genes.

basal-like designation, on the other hand, is based mostly on gene expression and is defined by its cellular origin (similar to basal cells of the milk ducts). Although the majority of triple-negative tumors (B70%) are basal-like, the two subtypes are not completely identical. However, the distinction between the two is not routinely made, and the two names are often mistakenly considered synonymous (Kreike et al., 2007; Prat et al., 2013; Stover et al., 2016). Owing to their characteristics (high grade, high proliferation index, and mitotic index) and lack of targeted therapies, the vast majority of triplenegative tumors are aggressive cancers with rapid development consequently

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leading to lymph node involvement frequently and large tumor size at diagnosis. CSTN is therefore associated with a poor prognosis. Moreover, many studies highlight the heterogeneity of this subgroup with histological (metaplastic carcinoma, apocrine carcinoma, ICC, CLI, myoepithelial carcinoma, etc.) and molecular (basal-like, claudin-low) variability, difference in disease progression, and variable expression of biomarkers (p53, cytokeratins, EGFR), which influence the prognosis of patients (Mills et al., 2018).

20.5.1 Epidemiology Among invasive breast cancers the incidence of triple-negative tumors ranges from 10% to 20% (Anders et al., 2008). TNBC is associated with a younger age at diagnosis, as the median age of affected patients is lower than that in other breast cancer subtypes. Several studies have also found ethnic differences with a higher incidence in African-American, Hispanic, and, more recently, Indian and Native American women ( Thakur et al., 2018; Thike et al., 2010). Data from the literature describe NSTC as the most aggressive subtype with a poor prognosis, including significant relapse and death rates (Li et al., 2017). Indeed, the majority of relapses occur within 3 years of initial treatment. Notably, the team of Bauer et al. showed that 5-year survival rates were significantly lower in patients with TNBC compared to other breast cancer subtypes, with 77% and 93% 5-year survival rates, respectively (Bauer et al., 2007). Similarly, relapse rates, and particularly metastatic relapse, are significantly higher in this subtype, especially in patients with tumor residue after neoadjuvant therapy. The metastatic sites diverge from the metastases that are observed in other types of breast cancers with preferential metastases in the visceral level (lungs and liver). In addition, a higher rate of brain metastases is particularly noticeable in this subpopulation (Dent et al., 2009). More generally, however, one of the major difficulties in identifying new targets is undoubtedly related to the heterogeneity of TNBC tumors. The work of Lehmann et al. showed that TNBCs can be classified into six molecular subtypes based on their transcriptome: (1) basal-like 1 (BL1), which is characterized by high expression of genes involved in the cell cycle and DNA damage response; (2) basal-like 2 (BL2), which is enriched in myoepithelial markers and gene products involved in growth factor signaling; (3) mesenchymal (M), which expresses genes involved in epithelial-mesenchymal transition, motility, and the growth factor pathway; (4) mesenchymal stem-like (MSL), which is close to the M subtype, differing from it by a low expression of genes involved in proliferation and by the expression of genes involved in angiogenesis and those associated with stem cells; (5) immunomodulatory (IM), which is characterized by the expression of cytokine genes and genes involved in immune signal transduction; and (6) luminal (LAR), which expresses luminal genes under the control of androgen receptor signaling. Cross-referencing the six TNBC subtypes identified by Lehmann et al. with the five breast cancer

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subgroups originally proposed by Perou et al. indicates that (1) TNBCs of the BL1, BL2, IM, and M subtypes belong to the basal-like group; (2) TNBCs of the LAR subtype cluster strongly with the HER2 group; and (3) TNBCs of the MSL subtype belong to the basal-like and normal breast
like groups (Mayer et al., 2014) (Fig. 20.8). Fig. 20.9 summarizes the main signal transduction pathways that play a fundamental role in the tumorigenesis processes as well as in the mechanisms of therapeutic resistance in TNBC. Table 20.1 shows the main biomarkers with their impact on prognosis or survival.

20.5.2 TP53 gene, p53 protein, and Ki-67 The tumor protein 53 (TP53) gene is located on chromosome 17 (17p13.1) and encodes the p53 protein, a transcription factor that suppresses tumor growth and is essential in the process of cellular response to DNA damage. When DNA damage occurs, there is an increase in p53 transcription, which TNBS subtype BL1 BL2 IM M MSL LAR LINC All TNBC

Samples (percentage) 27 (17%) 12(7%) 30(18%) 39(24%) 10(6%) 14(9%) 31(19%) 163(100%)

Median DFS 20.1 12.5 22.7 9.1 13.9 4.4 22.0 11.8

Median OS 21.1 8.4 24.8 9.5 20.9 5.7 24.9 15.2

FIGURE 20.8 Subtyping of TNBC tumors based on TCGA data. TNBC, Triple-negative breast cancer. Data from Mayer, I.A., Abramson, V.G., Lehmann, B.D., and Pietenpol, J.A. (2014). New strategies for triple-negative breast cancer
deciphering the heterogeneity. Clinical Cancer Research, 20, 782
790.

FIGURE 20.9 Key signal transduction mechanisms in TNBC tumorigenesis. TNBC, Triplenegative breast cancer.

TABLE 20.1 The main biomarkers with their impact on prognosis or survival. Molecular biomarker

Main function

Prognostic significance

Targeted therapies

References

TP53 gene

Apoptosis

Low gene expression in missense mutations of TP53 correlates with poor prognosis (worse disease-free survival (DFS), but there are conflicting data)

NA

Kim et al. (2016), Synnott et al. (2017)

Ki-67

Cell proliferation

Higher index and expression correlate with shorter DFS and overall survival

NA

Wang et al. (2016), Ilie et al. (2018)

EGFR

Cell growth

Increased expression is associated with worse DFS

Erlotinib, gefitinib, afatinib

Gumuskaya et al. (2010), Gluz et al. (2009)

c-KIT

Transformation and differentiation of cells

Predictor of poor cancer-specific survival in patients with TNBC

Imatinib

Jansson et al. (2014)

VEGF

Angiogenesis

High levels are associated with disease progression and metastasis rates

Bevacizumab

Linderholm et al. (2009)

Androgen receptor

Cell proliferation and dedifferentiation

Positive expression correlates with better disease-free survival; may be associated with chemoresistance

Bicalutamide, enzalutamide, abiraterone

Niemeier et al. (2010), He et al. (2012), Galal et al. (2013), Gucalp and Traina (2016), Wang et al. (2016)

BRCA1 and BRCA2 genes

Repair of DNA double-strand breaks

Mutated status correlates with increased DFS

PARP inhibitors olaparib

PD-L1 protein

Immune evasion process of tumors

High expression correlates with higher survival in checkpoint inhibitor trials

Immune checkpoint inhibitor tezolizumab

Notch pathway

Cell proliferation and differentiation

Potential target under development

AL101

PI3-kinase pathway

Cell proliferation

Multiple genomic alterations lead to activation of the PI3-kinase pathway, including activation of PIK3CA, AKT, and mTOR or inactivation of tumor suppressor genes such as PTEN

PI3K inhibitor alpelisib AKT inhibitors ipatasertib, capivaserti

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causes cell cycle arrest and DNA repair or cell death. This is effectively established through interaction with targets such as p21, cycle-dependent kinase (CDK), repair proteins (PARP, BRCA), and PTEN (Girardini et al., 2011; Walerych et al., 2012), (Di Agostino et al., 2006). The mutant p53 protein can exert aberrant functions, interacting differently with downstream targets, upregulating the CDK-1 and PI3K/AKT/mTOR pathway, and downregulating the tumor pathway, downregulating tumor suppressor proteins such as p63 and p73, stimulating cell proliferation, and subsequently evading apoptosis (Turner et al., 2013). The expression of p53 protein in TNBC tumor tissues can vary depending on the type of mutation that occurs in the TP53 gene. Patients with missense mutations tend to have a high expression of p53 protein, as they normally produce a more stable full-length protein, in contrast to patients with deletion mutations, who do not express the protein (Yemelyanova et al., 2011).Over the years, research has developed a number of molecular techniques to measure cell proliferation rates. One of these is the quantification of proliferation-related membrane antigens by immunohistochemistry (IHC). Ki-67, a protein encoded by the MKI67 gene (proliferation marker Ki-67 gene), is the most commonly used cell membrane antigen to determine cell proliferation and is therefore considered to be a prognostic biomarker in breast cancer, although its value is uncertain in the context of patients with TNBC (Blows et al., 2010; Viale et al., 2008). These tumors tend to have increased expression of Ki-67, with studies showing a prevalence of 44.7%
53.4% of tumors with Ki-67 expression greater than 20% (Nakagawa et al., 2011).

20.5.3 Epidermal growth factor receptor, c-KIT, and cytokeratins (CK 5/6, CK 14, CK 17, CK 56) Epidermal growth factor receptor (EGFR) is a member of a family of transmembrane glycoproteins with a tyrosine kinase domain that activates signal transduction pathways, playing an important role in cell proliferation and inhibition of apoptosis. The prevalence of EGFR overexpression in TNBC is highly variable across studies, ranging from 13% to 78% (Gluz et al., 2009; Gumuskaya et al., 2010), due to the lack of standardized measurements of IHC findings and wide demographic variation. Although some results suggest a strong association between higher EGFR gene copy number and poor survival, higher tumor grade, and axillary lymph node metastasis, data on EGFR overexpression in triple-negative cancers are controversial and have not been confirmed as a prognostic biomarker (Liu et al., 2012; Nakajima & Ishikawa, 2012; Park et al., 2014). Although EGFR overexpression is common in metastatic breast cancer, phase II studies evaluating the efficacy of EGFR inhibitors such as tyrosine kinase inhibitors (TKIs, gefitinib, afatinib, and erlotinib) and monoclonal antibodies (cetuximab and panitumumab) have not shown effective results (Albanell et al., 2019; Carey et al., 2012;

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Dickler et al., 2009). c-KIT (CD117) signaling is likely to play an important role in cell transformation and differentiation. Expression of c-KIT protein is de stained in approximately half of TNBC tumor tissues (Jansson et al., 2014). Aberrant activation of the c-KIT gene is part of the carcinogenesis process and metastatic mechanisms of various human malignancies. The study of hyperactivation and alterations in the c-KIT pathway is very interesting because it is potentially accessible to TKI treatment with imatinib, which is already traditionally used in the treatment of certain oncohematological diseases such as chronic myeloid leukemia as well as in solid tumors such as gastrointestinal stromal tumors and protuberant dermatofibrosarcoma (Shams & Shams, 2011).

20.5.4 Vascular endothelial growth factor Angiogenesis signaling, mediated by vascular endothelial growth factor (VEGF), is crucial in the process of tumor growth and spread. VEGF comprises a family of six proteins: VEGF-A, VEGF-B, VEGF-C, VEGF- D, VEGF-E, and placental growth factor. Alternative splicing of mRNA creates four isoforms, the most common being VEGF165. Mediators of gene expression include hypoxia, growth factor, nitric oxide, oncogenes, HER2, and tumor suppressor genes (Gerwins et al., 2000; Holmes & Zachary, 2005). VEGF is highly expressed in approximately 30%
60% of transverse breast cancer patients (Linderholm et al., 2009). In addition to VEGF, scoring of mean vascular density by IHC has been used as a prognostic biomarker in transverse breast cancer. Conceptually, high mean vascular density in breast cancer has been associated with poor prognosis and worse survival (Chanana et al., 2014).

20.5.5 Androgen receptor The androgen receptor (AR) is part of a complex of steroid hormone receptors that modulate transcription factors, controlling gene expression in different cellular processes, sometimes in a dualistic manner. ARs can stimulate both proliferation and dedifferentiation and can induce apoptosis and cell death, depending on which signaling pathways are activated simultaneously. Although early studies suggested a negative prognostic effect of AR in TNBC, more recent data have reaffirmed that patients with AR-positive TNBC have a more favorable outcome. Immunohistochemical expression of AR in TNBC can vary significantly between 10% and 90%, depending on the cohort (Galal et al., 2013; Gucalp & Traina, 2016; He et al., 2012; Niemeier et al., 2010).

20.5.5.1 Homologous recombination defect and BRCA1/BRCA2 mutations All cells in the human body undergo constant external assaults on the DNA machinery. However, they rely on an efficient DNA damage response

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mechanism. Double-strand breaks are severe forms of damage and are repaired by two main pathways: error-free homologous recombination and nonhomologous end joining (Jasin & Rothstein, 2013). Initially described in patients with mutations in the BRCA1 and BRCA2 genes, homologous recombination deficiency can occur in sporadic cancers through genetic and epigenetic inactivation of other components (PALB2, BARD1, BRIP1, RAD51B, RAD51C, RAD51D, ATM, FAAP20, CHEK2, FAN1, FANCE, FANCM, and POLQ), a condition defined as BRCAness (Lord & Ashworth, 2016). Tumors that are deficient in homologous recombination are likely to be more sensitive to platinum chemotherapy as well as inhibitors of the DNA repair enzyme, poly-ADP ribose polymerase 1 (PARP1) (Tan et al., 2008).

20.5.5.2 In situ hybridization of the mRNA More recent studies have focused on the tumor microenvironment as a determinant of survival, invasiveness, and metastasis in TNBC. Normal breast tissue typically does not contain immune cells, but breast tumor tissue and surrounding stroma may contain higher levels of immune cell infiltration. There is increasing evidence for the role of tumor lymphocyte immune infiltrates in TNBC. The concept of immunoevasion assumes that host immunity, depending on the peritumoral and intratumoral composition, can either stimulate tumor growth or eradicate disease, which is the basis for the definition of immunoevasion and immunogenicity, respectively. According to this idea, tumor cells are initially rejected by the immune system, and then surviving tumor cells persist in a dormant state and, after activating prosurvival pathways, express molecules that promote immune suppression and angiogenesis. Thus the elimination, equilibrium, and escape phases constitute the three stages of immunoediting (Ryungsa, 2007). CD4 and CD8 helper T cells are part of the proinflammatory complex of type 1 immunity necessary for the elimination of tumor cells. Cells of the innate immune system (neutrophils, monocytes, macrophages, and antigenpresenting cells) and adaptive system (B and T lymphocytes) are essential for rapid recognition and response to pathogens as well as to nonself or tumor antigens. Many antigens that are present in the breast cancer cell membrane can activate and stimulate T cells, inducing a regulatory immune response. However, the ability for immune suppression is essential for the survival of normal cells (American Society of Clinical Oncology Educational Book, 2015). Tumor-infiltrating lymphocytes (TILs) are highly expressed in approximately 20% of TNBC cases. Some studies have suggested that TILs in breast cancer may be a surrogate biomarker for the adaptive immune response, particularly for the TNBC subtype, which is considered one of the most immunogenic. There is a consensus that the cytotoxic effect of chemotherapy is partly influenced by the immune response against tumor cells.

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Similarly, chemotherapy can provide an enhanced immune response by altering the microenvironment and increasing tumor immunogenicity, resulting in tumor shrinkage (DeNardo & Coussens, 2007; Schmidt et al., 2008). The antitumor activity of immune checkpoint inhibitors has been extensively studied in TNBC. Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that limits the action of effector T cells within tissues, thus playing a crucial role in the process of immune evasion of tumors. The two ligands of PD- 1, with distinct expression profiles in tumor types, are PD-L1 and PD-L2 (Ishida et al., 1992). Regulation of PD-L1 can occur through several processes, including response to IFN-gamma action, oncogenic signaling, and deletion or silencing of PTEN with consequent overexpression of the PI3K pathway. Immunotherapy with PD-1 and PD-L1 inhibitors results in T cell activation, restoring host antitumor immune activity, demonstrating sustained activity and increased survival in selected tumors.

20.6 Conclusion Several viruses have already been implicated in the development of cancer in humans. The mechanisms that explain the development of these cancers are progressively better understood, even if many gray areas remain, owing to the frequent interaction of different cofactors. Indeed, viruses are sometimes only one of the links in a long chain in which genetic, environmental, or other factors may intervene. To better understand the pathophysiology of HPV involvement in breast tissue carcinogenesis, it would be interesting in the future to analyze the presence of this virus in benign lesions as well as in precancerous lesions (atypical dysplasia) of the breast and carcinomas in situ. It would also be important to study the correlation of this virus with other oncogenic viruses such as EBV and mouse mammary tumor virus in the development of breast cancer, which will lead to the development of new treatments in the future There is no doubt that recent progress has been made in understanding TNBC as a disease with intrinsic molecular and immunological heterogeneity, recognizing the variety of clinical phenotypes. This new scenario requires an urgent comprehensive subclassification that incorporates immunomolecular signatures for more targeted and effective treatment. Although PARP inhibitors and checkpoint inhibitors have recently been incorporated in some settings, cytotoxic chemotherapy remains the mainstay of TBC treatment, resulting in different outcomes for patients with similar clinicopathological features. The role of a more comprehensive accessible panel of immunohistochemical biomarkers has improved treatment decisions in breast cancer. In addition, new biomarkers have been proposed to predict survival and response to chemotherapy in many cases, allowing personalized approaches such as the need for dose escalation as well as the incorporation

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of new antitumor agents into the standard regimen. On the other hand, more modern next-generation sequencing
based biomarkers still need to be better validated by reliable prospective studies and become more accessible to daily practice. Once considered an inaccessible disease by molecular therapy, transgenic breast cancer has recently been successfully studied for incorporation of novel targeted therapies due to improvements in response predictions. Given the proposed subtypes with their molecular variations defined by specific biomarkers, the incorporation of platinum agents, checkpoint inhibitors, and PARP inhibitors, great strides have been made in both neoadjuvant treatment and the approach to metastatic disease.

Acknowledgments The authors would like to thank the Minister of National Education, Professional Training, Higher Education and Scientific Research, and many thanks to the members of the Virology, Oncology and Medical Biotechnology team at FSTM-Hassan II University of Casablanca for all their efforts to support us during all work stages on this research

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Chapter 21

Hypermethylation of tumor suppressor genes associated with Helicobacter pylori and Epstein
Barr virus infections in gastric cancer Fatima Ezzahra Rihane1,2, Driss Erguibi3, Farid Chehab3 and Moulay Mustapha Ennaji2 1

Laboratory of Genetic and Molecular Pathology, Faculty of Medicine & Pharmacy Casablanca, University Hassan II of Casablanca, Casablanca, Morocco, 2Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco, 3Service of Digestive Cancers Surgery and Liver Transplant, Department of Surgery, Ibn Rochd University Hospital Center, Faculty of Medicine & Pharmacy Casablanca, University Hassan II of Casablanca, Casablanca, Morocco

21.1 Introduction Gastric cancer is the most prevalent malignancy in the world (Rawla & Barsouk, 2019). Despite reductions in frequency and mortality rates in recent decades, it is still the fifth most common cancer and the third leading cause of cancer death worldwide, with an estimate of 1,033,701 new cases and 782,685 deaths related to gastric cancer in 2018 (Bray et al., 2018). Gastric cancer is a cancer of recognized infectious etiology involving bacteria and viruses, including Helicobacter pylori and Epstein
Barr virus (EBV), which remain among the main well-established causes of gastric cancer. The mechanism by which H. pylori induces gastric adenocarcinoma is multiple and involves complex interactions between H. pylori
specific virulence factors (e.g., CagA), the host genotype (e.g., IL-1B polymorphisms), and environmental factors (e.g., a high-salt diet) (Amieva & Peek, 2016; Wu, Cho, et al., 2010). Moreover, EBV is considered to be a direct Oncogenic Viruses Volume 1. DOI: https://doi.org/10.1016/B978-0-12-824152-3.00009-3 Copyright © 2023 Elsevier Inc. All rights reserved.

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transforming pathogen through the expression of its own death or proliferation regulatory genes, and it has been classified as a type I carcinogen by the International Agency for Research on Cancer (Frappier, 2012; Saha & Robertson, 2013; Shair et al., 2012). EBV can induce gastric epithelial cell death or persist as a latent infection and promote cancer progression (Liang et al., 2014). Recent progress in cancer epigenetics, including DNA methylation, histone modifications, chromatin remodeling, and microRNAs, have shed new light on the importance of epigenetic deregulation in gastric tumors associated with H. pylori and EBV (Cheng et al., 2013; Muratani et al., 2014; Wu, Lee, et al., 2010). DNA methylation is a major cause of gene silencing, occurring through a methyl radical addition to the cytosine base adjacent to guanine. Most DNA methylation events occur in CpG dinucleotides, especially in those located in gene promoters (Wang & Leung, 2004). DNA methylation is described as one important method of gene regulation that normally occurs in imprinted genes, X-chromosome inactivation, and silencing of tumor suppressor genes, among other situations (Bird, 2002). Approximately 400 genes that are actively expressed in normal gastric epithelial cells are estimated to be inactivated in gastric cancers as a result of hypermethylation of the CpG island present in their promoters (Kang, 2012). Methylation in tumor suppressor genes and those encoding molecules involved in regulating cell cycle, cell adherent/invasion/migration, cell growth, apoptosis, and so on is one of the most well-defined epigenetic alterations implicated in gastric carcinogenesis (Qu et al., 2013). Aberrant CpG island hypermethylation occurs early in the multistage gastric carcinogenesis and tends to increase with the stepwise progression of the malignancy (Cheng et al., 2013). In addition, some studies have linked DNA hypermethylation to H. pylori-cagA 1 and EBV infection, geographical location, and environmental exposure (Ferrasi et al., 2010). In this chapter, we focus on recent studies of hypermethylation of tumor suppressor genes that are associated with H. pylori and EBV infections in gastric carcinogenesis.

21.2 DNA methylation in gastric carcinogenesis DNA methylation is the most common epigenetic aberration and the main cause of gene silencing, occurring through a methyl radical addition to the cytosine base adjacent to guanine (Feinberg & Tycko, 2004; Padmanabhan et al., 2017). DNA methylation in mammalian cells is regulated by a family of DNA methyltransferases (DNMTs) that catalyze the transfer of methyl groups from S-adenosyl-L-methionine to the 50 position of cytosine bases in the CpG dinucleotide (Kinney & Pradhan, 2011). DNMTs are key components of the cellular CpG methylation machinery, including mainly DNMT1, DNMT3A, and DNMT3B, which are responsible for the maintenance and alteration of methylation in human cells (You & Jones, 2012). DNMT1 is a

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maintenance methyltransferase, while DNMT3A and DNMT3B, which are expressed throughout the cell cycle, establish new patterns of DNA methylation in early development (Sharma et al., 2010; Song et al., 2012). Most DNA methylation events occur in CpG dinucleotides, especially in those located in gene promoters (Wang & Leung, 2004). The CpG islands in the promoter regions are basically unmethylated, and gene expression is regulated by histone modification. Aberrant methylation of promoter CpG islands causes transcriptional silencing, which leads to downstream gene expression. Methylation-induced silencing of tumor suppressor genes is one of the main mechanisms of carcinogenesis (Feinberg & Tycko, 2004; Padmanabhan et al., 2017; Vogelstein et al., 2013). Moreover, the DNA methylation level is affected by environmental factors. Previous studies showed that aging and smoking are involved in the accumulation of aberrant methylation in CpG islands (Christensen et al., 2009). In addition, chronic inflammation is known to accelerate the accumulation of aberrant methylation in noncancerous tissues. For example, ulcerative colitis, chronic hepatitis, and reflux esophagitis cause inflammation, leading to aberrant CpG island methylation (Matsusaka et al., 2014). This aberrant CpG island methylation of these noncancerous tissues is considered to be associated with carcinogenesis (Katsurano et al., 2012). Chronic inflammation caused by H. pylori is associated with gastric carcinogenesis (Matsusaka et al., 2014). H. pylori infection causes aberrant promoter methylation, silencing the expression of tumor suppressor genes such as RUNX3, LOX, and CDH1 (Muhammad et al., 2019). Previous studies suggested that chronic inflammation caused by H. pylori infection, rather than any factor of H. pylori itself, may induce aberrant DNA methylation (Niwa et al., 2010). Another study using a Mongolian gerbil model supported that both H. pylori infection itself and aberrant methylation in gastric mucosa contribute to H. pylori
related gastric carcinogenesis (Niwa et al., 2013).

21.3 Helicobacter pylori and Epstein
Barr virus inducing aberrant methylation in the promoter of tumor suppressor genes 21.3.1 Helicobacter pylori inducing aberrant methylation in the promoter of tumor suppressor genes H. pylori infection has been known to cause gastric carcinogenesis, and it has been associated with chronic inflammation, accumulation of reactive oxygen/ nitrogen species with subsequent oxidative/nitrosative DNA damage, and silencing of tumor suppressor genes via epigenetic modification (Nardone & Compare, 2008). H. pylori infection has been reported to increase aberrant DNA methylation in the gastric mucosa, which contributes to an increased risk of gastric cancer (Maekita et al., 2006; Nakajima et al., 2009). Rates of metastasis and recurrence have been found to be higher in H. pylori
positive cancer

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patients with aberrant DNA methylation than in those without (Liu et al., 2012). Eradication of H. pylori infection has been found to decrease overall methylation levels in patients with gastritis (Nanjo et al., 2012). H. pylori
related methylation alters the function not only of common oncogenes or tumor suppressor genes, but also other genes involved in cell growth and differentiation (Cheng et al., 2013; Lu et al., 2012; Peterson et al., 2010). H. pylori methylation is also associated with the development of other genes; for example, E-cadherin, a cell adhesion molecule that is responsible for maintaining the epithelial phenotype, is considered to be an invasion suppressor gene (Yoshiura et al., 1995). Methylation of the E-cadherin gene is present in nonneoplastic H. pylori
infected gastric mucosa and in gastric carcinoma, particularly in poorly differentiated adenocarcinoma (Chan et al., 2006). E-cadherin methylation can be reversed after H. pylori eradication (Chan et al., 2006). H. pylori strains that express high levels of CagA, which is a virulence factor produced by H. pylori and is known to be involved in the methylation of certain tumor suppressor genes, more strongly suppressed p53 expression compared to low-risk strains (Wei et al., 2015). Degradation of p53 is prevented by the human tumor suppressor protein p14ARF by binding to the MDM2-p53 complex (Palmero et al., 1998). CagA has been shown to decrease the accumulation of p14ARF by hypermethylation or deletion of the gene coding for this tumor suppressor (Wei et al., 2015). Therefore CagA induces p53 degradation via hypermethylation of p14ARF (Wei et al., 2015). Transcription factor forkhead box d3 (FOXD3) plays a key role in early embryonic development and is considered a novel tumor suppressor (Hanna et al., 2002). Knockdown of FOXD3 promotes growth, migration, invasion, and angiogenesis in various cancers (Chu et al., 2014). FOXD3 methylation was found to be increased in gastric tissues of H. pylori
positive gastritis patients compared to normal uninfected individuals (Cheng et al., 2013). In addition, FOXD3 promoter methylation was significantly elevated to a similar degree in intestinal metaplasia but to an even higher degree in gastric cancer (Cheng et al., 2013). In addition, the expression of the proapoptotic genes CYFIP2 and RARB, downstream target molecules of FOXD3, was also suppressed in gastric samples (Cheng et al., 2013). Therefore downregulation of FOXD3 by H. pylori
mediated hypermethylation interrupts the balance between cell death and survival (Cheng et al., 2013).

21.3.2 Helicobacter pylori inducing aberrant methylation in the promoter of tumor suppressor genes via chronic inflammation Chronic inflammation is a well-known factor that is responsible for the promotion of many cancers (Peek & Crabtree, 2006; Yasmin et al., 2015). Approximately 15%
20% of all human malignancies are related to chronic inflammation (Kuper et al., 2000). Gastric cancer is a typical inflammationassociated malignancy, closely related to chronic inflammation induced by

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FIGURE 21.1 Helicobacter pylori inducing methylation in the promoter of tumor suppressor genes via inflammation.

H. pylori in the gastric mucosa. Chronic inflammation caused by H. pylori infection is considered to be an inducer of aberrant DNA methylation (Niwa et al., 2010). The expression levels of several inflammation-related genes (e.g., CXCL2, interleukin 1 beta (IL-1β), nitric oxide synthase 2, and tumor necrosis factor alpha) correlate with temporal changes in methylation levels (Niwa et al., 2010). Inflammation induced by H. pylori infection is associated with an increase in inducible nitric oxide/nitric oxide synthase expression via IL-1β production, which is a prototypical proinflammatory cytokine. This cytokine induces hypermethylation of the E-cadherin promoter (Fig. 21.1) (Qian et al., 2008). In addition, IL-1β stimulates methylation of the antiinflammatory cytokine transforming growth factor-β1 (TGF-β1) promoter in human gastric epithelial cells (Wang et al., 2013). TGF-β1 promoter methylation is higher in H. pylori
positive gastric mucosal tissues than in H. pylori
negative gastric mucosal tissues, and also increased in gastric cancerous tissues (Wang et al., 2013).

21.3.3 Epstein
Barr virus inducing aberrant methylation in the promoter of tumor suppressor genes Detection of EBV in a subset of gastric cancers was first reported in 1992 by the uniform presence of EBV in all gastric cancer cells but not in adjacent normal cells (Shibata & Weiss, 1992). Since then, numerous reports have shown this strong association, and the role of EBV in gastric carcinogenesis has been recognized as (Herrman & Niedobitek, 2003; Zur Hausen et al., 2004).

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The mechanism underlying EBV infection in the gastric mucosal epithelium remains unclear, while the viral receptor molecule CD21 in B cells is not expressed on epithelial cells (Yoshiyama et al., 1997). Coculture of virusproducing lymphocytes demonstrates a much higher infection efficiency (up to 800-fold) compared to cell-free infection, so direct contact between B cells and gastric epithelial cells is the most likely model to explain how EBV infects epithelial cells in vivo, this hypothesis supports the histopathological evidence that the basal mucosa of EBV 1 gastric cancer shows atrophic gastritis with lymphocytic infiltration due to H. pylori infection. (Imai et al., 1998) However, it remains unclear whether chronic inflammation due to H. pylori is a prerequisite for EBV infection of gastric epithelial cells (Matsusaka et al., 2014). EBV-infected cells are characterized by different patterns of latent gene expression. There are three different forms of EBV latency (I, II, and III), each with a distinct pattern of gene expression (Young & Murray, 2003). However, these different types of latency are controlled by the epigenetic regulation of various EBV promoters (Ambinder et al., 1999). EBVaGC shares the same type I latency as Burkitt lymphoma, with expression of EBER, EBNA1, Barts, LMP1, LMP2A and BARF1 (Fukayama et al., 1994; Strong et al., 2013; Uozaki & Fukayama, 2008). Functional studies show that these viral genes are involved in the oncogenic modulation of host gene expression, including components of the cellular CpG methylation machinery (Li et al., 2005). LMP1 and LMP2A are well-documented EBV oncogenic proteins that play a critical role in tumor transformation of epithelial and lymphoid cells. LMP1 can activate several cell signaling pathways, including the nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB), Janus kinase/signal transducers and activators of transcription 3 (JAK/STAT3), c-Jun N-terminal kinase and activator protein 1 (JNK/AP-1), and phosphatidylinositol 3-kinase (PI3K)/AKT signaling (Fig. 21.2) (Tsai et al., 2002). The LMP1 protein, via its carboxy terminal activation region-2, the last three amino acid domains (CTAR2-YYD), can upregulate DNMT1, DNMT3a, and DNMT3b transcripts via the activation of JNK signaling (Tsai et al., 2006; Tsai et al., 2002). LMP1 also promotes DNMTs to form transcriptional complexes with methyl CpG-binding protein 2 (MeCP2) and histone deacetylase 1 (HDAC1) on the E-cadherin promoter, whereas a JNK inhibitor prevents this complex formation (Tsai et al., 2006; Tsai et al., 2002). Activated DNMT1 then methylates and represses cellular promoters such as E-cadherin and docking protein 1 (DOK1) in cells expressing LMP1 (Siouda et al., 2014; Tsai et al., 2002). DNMT enzyme activity is also elevated twofold to threefold in epithelial cells expressing LMP1 (Tsai et al., 2002). LMP2A also activates several cell signaling pathways, including JAK/STAT3 and PI3K/AKT signaling, which further regulate DNMT and other epigenetic modifiers during EBVaGC pathogenesis (Kong et al., 2010). LMP2A could

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FIGURE 21.2 EBV infection inducing methylation in epithelial cells (Stanland & Luftig, 2020).

positively regulate the expression of DNMT1, DNMT3b, and BMI1 at transcriptional and protein levels (Hino et al., 2009; Kong et al., 2010). LMP2A upregulates DNMT1 expression by inducing STAT3 phosphorylation independently of IL-6 stimulation, which further causes PTEN methylation and silencing in EBVaGC (Hino et al., 2009). EBNA1 as a viral nuclear protein is consistently expressed in all EBV associated tumors (Wang et al., 2010). EBNA1 binds to the latent origin of EBV replication (OriP), which is essential for replication and maintenance of the EBV genome during its latency (Leight & Sugden, 2000; Sugden & Warren, 1989). EBNA1 is a DNA-binding protein localized to the cell chromatin via its chromosome-binding domains (Kanda et al., 2013). Chromatin immunoprecipitation sequencing (ChIP-Seq) studies have uncovered the genome-wide binding profile of EBNA1 to its target genes, including modulators of the cellular methylation machinery, such as histone deacetylase 3 (HDAC3), indicating that EBNA1 can directly interfere with the CpG methylation machinery (Canaan et al., 2009; Lu et al., 2010).

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21.4 Helicobacter pylori coinfection with Epstein
Barr virus inducing aberrant methylation The interaction between H. pylori and EBV in the gastric mucosa may have synergistic effects in the development of gastric cancer. Many tumor suppressor genes have been found to be methylated in H. pylori and EBV coinfected gastric cancer (Ferrasi et al., 2010). In addition, H. pylori
positive individuals have a significantly higher EBV DNA load, suggesting a role for H. pylori in the conversion of EBV to the lytic phase (Minoura-Etoh et al., 2006). Similarly, EBV DNA load was higher in gastric cancer patients with H. pylori than in those without infection (Shukla et al., 2011). Two possible mechanisms are thought to exist, firstly an additional inflammatory response in case of coinfection and an increase in tissue damage caused by both H. pylori and EBV. A study in pediatric patients demonstrated that coinfection with EBV and H. pylori affected the severity of inflammation (CardenasMondragon, 2013). The second mechanism is based on gene product interaction that is more prominent between EBV and H. pylori. An in vitro study showed that EBV reactivation occurs through the PLC γ signaling pathway and that H. pylori CagA toxin strongly activates PLC γ (Churin et al., 2003) and also activates several kinases (Brandt et al., 2009). H. pylori CagA toxin and EBV LMP1 and LMP2 activate NF-κB and MAP kinases, which then regulate DNMT and other epigenetic modifiers (Hino et al., 2009; Tegtmeyer et al., 2011; Tsai et al., 2006).

21.5 Conclusion Aberrant DNA methylation plays a central role in carcinogenesis. In gastric cancer, two etiological agents, H. pylori and EBV, contribute to carcinogenesis through the induction of aberrant methylation in gastric epithelial cells, although further studies are needed to elucidate the detailed molecular mechanisms underlying the induction of promoter methylation in response to H. pylori and EBV infection, understanding these mechanisms could clarify the process of gastric carcinogenesis, and application of this knowledge to clinical use could facilitate diagnosis, risk management, and prevention.

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Chapter 22

Etiology of human papillomavirus in cervical cancer and infection mechanism Abderrahim Hatib, Rihabe Boussettine, Najwa Hassou and Moulay Mustapha Ennaji Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco

22.1 Introduction Cervical cancer (CC) is a localized primary or secondary malignant proliferative process at the level of the uterine cervix. It is the second most common female cancer in the world. According to World Health Organization forecasts, 500,000 new cases are diagnosed each year, of which 83% are in developing countries (Ahmad & Ansari, 2021). In Morocco CC is a real public health problem with an estimated 6000 new cases and 3000 CC-related deaths per year (Del Lo et al., 2021). It is well established that the human papillomavirus (HPV) is the main cause of CC. Other sexual and nonsexual factors are involved, such as cofactors in the progression of HPV infection to CC (Jit et al., 2021). According to the HPV International Reference Center (http://www.hpvcenter.se, 2 January 2015 until consultation 2015), HPV families represent 202 different genotypes. More than 40 HPVs that are known to infect the female genital tract have been identified and sequenced (Ibragimova., 2021), including HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82. These genotypes are classified as high-risk HPV (HR HPV) according to their oncogenic potential. Wolbmers et al. reported in 1999 that a 99.7% rate of HPV infection was recorded in women with CC. HPV 16 and 18 are the most common genotypes globally, causing more than 70% of CC cases (Chen, Liu, et al., 2020; Chen, Zhang, et al., 2020; Hashim et al., 2020). The rest of the genotypes were classified as low-risk HPV (6, 11, 28, 32, 40, 42, 43, 44, 54, 55, 57, 61, 62, 71, 72, 74, 81, 83, 84, 86, 87, 89, etc.) or possible HR HPV (68, 26, 53, 66, 82, 70, Oncogenic Viruses Volume 1. DOI: https://doi.org/10.1016/B978-0-12-824152-3.00022-6 Copyright © 2023 Elsevier Inc. All rights reserved.

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67, and 73) (Heard et al., 2013). Many studies have shown that the prevalence and distribution of these two types vary according to geographical area, population, and cytological status (Vidal et al., 2011). The objective of this chapter is to provide an overview on HPV, including its genomic organization, its structure, the viral cycle, and mechanisms in the induction of CC.

22.2 Human papillomavirus cervical cancer risk factors Several fundamental and epidemiological studies have been carried out with the aim of understanding the main risk factors that are involved in the genesis of CC (Andrew et al., 2021). CC is a multifactorial disease with the entanglement of several cofactors, including human papillomavirus infection, which is most often increased by lack of vaccination or poor management screening (Desai et al., 2022). The HPV virus is preferentially transmitted by sexual contact; it is the most common sexually transmitted viral infection in the world. Nearly 75% of sexually active women aged 15
44 years have encountered or will encounter the virus at some point in their sex lives (Zulaika et al., 2021). This infection is in the vast majority of cases inapparent, the virus being eliminated spontaneously by the immune system (McBride, 2021).But in some cases, the virus can evade the immune system, causing persistent of the infection, which may lead to the development of intraepithelial lesions of the cervix and uterus, which can progress to more severe high-grade lesions or even CC. It has been established that persistent infections with oncogenic HPVs are closely correlated with the occurrence of CC; HPV DNA is found in almost 100% of cases (Mantoani et al., 2021). Among the oncogenic HPVs, HPV 16 and 18 are the most carcinogenic types, responsible for more than 50% of cervical intraepithelial neoplasia
positive (CIN 21) precancerous lesions and 70% of CC cases in the world (Gupta et al., 2021). After HPV 16 and 18, the HPV 33, 45, and 31 types are less frequent but have been proven to be responsible for the appearance of precancerous and cancerous lesions of the cervix. HPVs 16, 18, 31, 33, and 45 represent more than 80% of the types involved in CCs in the world. In the latest data on the distribution of HPV genotypes, this figure reaches 86%, particularly for cancers of the cervix in Europe.

22.3 Viral etiology of cervical cancer Globally, epidemiological studies have shown that certain types of HPV are strongly associated with the development of high-grade lesions and CC. Some HPVs are more associated with the persistence and progression of CC than others. The most common genotype in cancer is the oncogenic HR HPV (Yete et al., 2018; Purwanto et al., 2020). HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 are associated with dysplastic or severe

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intraepithelial lesions, CIN 3, and invasive carcinoma (Walboomers et al., 1999; Wang et al., 2018). Publications have revealed the contribution of multiple HPV types to CC in multiple regions of the world. The involvement of different types of HPV in CC has been demonstrated (Li et al., 2010).

22.4 Biology of papillomavirus 22.4.1 Structural and genomic organization of human papillomavirus HPV is a virus of the Papillomaviridae family. More than 200 HPV types or genotypes have been identified in human species, distributed in the genera alpha, beta, gamma, mu and nu. Schematically, HPVs of the genus beta, gamma, mu, and nu are tropic to the skin, while HPVs of the alpha genus infect the skin or mucous membranes (Giuliani et al., 2021). Their genome is in the form of circular double-stranded deoxyribonucleic acid and measures approximately 8000 base pairs. It encodes a small number of proteins (eight proteins for HPV 16) divided into early proteins (E1, E2, E4, E5, E6, and E7) and late proteins (L1 and L2). Early proteins are involved in the regulation of viral replication. When their expression is deregulated (which can be observed for high-risk HPVs), the two proteins E6 and E7 behave as real oncogenes for the cell. The two late proteins (L1 and L2) are the structural proteins that form the capsid of the virus (Hoai et al., 2021). Fig. 22.1 shows the genomic organization of the HPV genome. In cancer cases, E6 and E7 are expressed throughout the infected epithelium, and no virions are produced (Mir et al., 2021). The L1 gene carries a conserved region, flanked by PCR primer sites MY09 and MY11. This region is the target of PCR designed to identify HPV in clinical samples. A test targeting the E6/E7 region may be preferred for established cancer cases, as it is always present in malignancies (Hoai et al., 2021). The production of HPV is associated with the keratinocyte differentiation program. In warts, papillomas, and mild to moderate dysplasia, viral DNA is episomal, and virion production is observed in the uppermost layers of infected epithelial cells. In highly dysplastic and cancerous lesions, viral DNA is integrated into the host cell chromosome. Integration is random in cellular chromosomes but often occurs in early regions of viral DNA, disrupting the E2 open reading frame and dysregulating expression of viral oncoproteins E6 and E7 (Cosper et al., 2021). The E7 protein induces cell proliferation and disrupts cell cycle regulation by inactivating proteins of the retinoblastoma family, while E6 of HR HPV blocks cell apoptosis by inducing the degradation of p53 (tumor suppressor). E7 and E6 are the only HPV proteins that are consistently expressed in CCs. They therefore represent the main tumor antigens that are targeted by immunotherapy. HPV-positive cancer cells are nonpermissive for virus production. They express cell proliferation markers and show chromosomal rearrangements (Santacroce et al., 2021).

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FIGURE 22.1 Genomic organization of the human papillomavirus genome. Schematic representation of the HPV16 circular genome showing the location of the early (E) and late genes (L1 and L2) and of the long control region. The HPV genome encodes eight well-characterized proteins, whose functions are indicated. Among them are the viral replication proteins E1 and E2 (blue) and the viral oncogenes E6 and E7 (pink), all of which have been validated as essential for viral pathogenesis and represent genuine targets for small molecule
based approaches for the treatment of HPV-associated diseases (Ferreira et al., 2020).

22.4.2 Viral Infection and expression of viral oncoproteins The general mechanism of pathogenesis of HPV is linked to the oncoprotein E6, which binds and induces the degradation of the tumor suppressor protein p53 (Santacroce et al., 2021). The viral proteins E7 and E6 inactivate the main tumor suppressors, p53 and the retinoblastoma protein, respectively. E6 protein is an activate telomerase that cooperates with E7 protein to inhibit apoptosis of human primary epithelial cells (Yugawa & Kiyono, 2009). E6 and E7 proteins cause oncogenesis of HPV by altering cell cycle control, and E2 protein is involved in viral and cellular transcriptional control (Cosper et al., 2021). Because of the low number of episomal copies, the virus retains its genome in the basal cells after infection. The expression of viral genes in these cells is not very well defined, but it is accepted that the two proteins E1 and E2 are sufficient for the maintenance of viral DNA in episomal form and to facilitate its segregation during cell division via Brd4 (Cosper et al., 2021).

22.4.2.1 Viral cycle of human papillomaviruses The viral cycle of HPV viruses and its main stages are shown in Fig. 22.2, illustrating the involvement of E6 and E7 oncogenes in carcinogenesis.

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FIGURE 22.2 The essential stages of the viral cycle, such as attachment, entry, decapsidation, or assembly and exit of the virus (Ferreira et al., 2020).

22.4.2.1.1

The encounter and attachment of the virus and the target cell

The first stage of infection is the encounter of the virus and the target cell. The attachment of the virus to the cell occurs, following the recognition between an antigenic motif present on the surface of the virus (proteins L1 and L2 of the capsid) and a surface receptor that is specific for the viral protein present on the surface of the cell target. Expression of this receptor in the infected individual is often limited to certain types of cells or tissues. The receptor is therefore generally a crucial determinant of the tropism of a virus (Sitz, 2021).

22.4.2.1.2 Entry and decapsidation The entry and decapsidation steps result in the release of the viral genome into the target cell. During entry of the viral genome into the cell, it is partially or totally stripped of the proteins that protected it in the virion; this stripping process is called decapsidation. The genome that ends up in the nucleus of the cell can be free or integrate into the chromosomes of the infected cell (as is the case for cells in precancerous and cancerous lesions) (Turashvili et al., 2021).

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22.4.2.1.3 Expression of viral genes and amplification of the viral genome Within the cell the viral genome plays two distinct roles. On the one hand, it is used to ensure the expression of viral proteins necessary for the replication of the virus and then for the formation of new viral particles. On the other hand, it is replicated before being packaged to form new viral particles (Lahmamssi et al., 2020). 22.4.2.1.4 Assembly and release of newly formed virions The canonical nuclear localization sequences, contained in the two structural proteins of the papillomavirus, L1 and L2, facilitate the translocation of proteins into the nucleus where assembly occurs. L2 expression and nuclear localization in suprabasal cells, for most high-risk human papillomaviruses (HPVs), appear to precede L1 expression.

22.5 Interaction between E6 and p53 in the cancer pathway 22.5.1 P53 and cell cycle control The progression of the cell cycle is controlled in a very rigorous way. It can be blocked at four main points (R, S, T, and A), which operate during phases G1, S, G2, and M. In principle, these are points of no return; once they have been crossed, the progression in the cycle continues, whatever happens (Hume et al., 2020). The first (R) prevents entry into the S phase. Once this obstacle has been overcome, the cell is allowed to replicate its DNA. But the replication can stop at the second checkpoint (S) if it does not proceed correctly (Ciardo et al., 2019). The third checkpoint (T) prohibits the cell from entering mitosis. The fourth point (A), also called the spindle checkpoint, prevents mitosis from being completed; the chromosomes cannot migrate to the poles of the mitotic spindle and separate into two batches, as occurs during normal anaphase (Saldivar et al., 2018) (Fig. 22.3). The transitions between the G1/S and G2/M phases of the cell cycle are under the biochemical control of the cyclin family of proteins. Cyclins function

FIGURE 22.3 Cell cycle and associated checkpoints.

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by binding and activating cyclin-dependent kinases (CDKs) (Roskoski., 2019). Their name derives from the fact that they are periodically synthesized and destroyed in synchrony with the cell cycle. The functions of p53 in the cell cycle include the control of the G1/S transition of the cycle. This control is done by blocking the activity of the cyclin-CDKs complexes, which causes the cycle to stop at the G1/S transition (Hume et al., 2020).

22.6 Consequences of the E6 and p53 interaction The oncoprotein E6, by binding to p53, contributes to the degradation of the latter with, as a consequence, an alteration of the regulatory function of the cell cycle. In cells that have been transformed with HPV16 or 18, p53 levels are very low (Celegato et al., 2022) (Fig. 22.4). According to Al Moustafa et al. (2004), MAE6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells (Fig. 22.5). The E6 protein alone is capable of immortalizing cells. On the other hand, the transformation of keratinocytes by papillomaviruses requires the activity of a second protein, protein E7 (Cosper et al., 2021). Fig. 22.6 summarizes all of the activities of the E6 oncoprotein.

FIGURE 22.4 Expression of the p53 protein (Western blot) and of a control protein GAPDH in NOE cells (human epithelial cells, buccal epithelium).

FIGURE 22.5 Effect of oncoprotein E6 on telomerase activity. HPV E7 contributes to the telomerase activity of immortalized and tumorigenic cells and augments E6-induced hTERT promoter function (Liu et al., 2008).

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22.7 Interaction between E7 and pRb in the cancer pathway The retinoblastoma susceptibility gene (Rb) is one of a family of genes known as tumor suppressor genes that regulate the cell cycle (Chen, Liu, et al., 2020; Chen, Zhang, et al., 2020). Fig. 22.7 describes the role of the Rb protein during the cell cycle.

FIGURE 22.6 Mechanisms of oncoprotein E6.

FIGURE 22.7 Role of Rb protein during the cell cycle.

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The E7 oncoprotein binds specifically to the hypophosphorylated form of pRb, releasing E2F (Fig. 22.8). E2F can then constitutively activate the genes necessary for the G1/S transition and induce a dysregulation of the cell cycle (S´anchez-Camargo et al., 2021). Fig. 22.9 presents a balance sheet of the activities of oncoprotein E7.

22.8 Assessment of the joint action of oncoproteins E6 and E7 Induction of aberrant proliferation by oncoprotein E7 is an apoptosis-inducing signal that is blocked by the actions of oncoprotein E6 (Ezebialu et al., 2021). The effective cooperation of these two oncoproteins immortalizes the cells, and this process is amplified by the action of the oncoprotein E5. The ability of E6 and E7 oncoproteins to target regulators of proliferation, apoptosis, genomic stability, and immortalization leads to the emergence of a clonal population of cells

DNA replication Cell division

E2F

1 : E2F drives cell replication and division

2 : Binding of RB to E2F prevents replication and cell division

E2F

DNA replication Cell division

Rb

DNA replication Cell division

E2F

3 : Binding of E7 to RB releases E2F and drives replication and cell division again

Rb

E7

FIGURE 22.8 Mode of action of E7.

FIGURE 22.9 Review of oncoprotein E7 activities.

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FIGURE 22.10 Molecular mechanisms by which papillomavirus oncoproteins cooperate to induce cervical carcinogenesis.

that have a propensity for transformation and tumor progression (Patrick., 2020) (Fig. 22.10).

22.9 Vaccination is a way to fight against cervical cancer HPVs are transmitted during sexual intercourse. The majority of men and women are infected with papillomaviruses during their lifetime, and the infection most often goes unnoticed. Women who started their sex life very young and those who have had many sexual partners are at a higher risk of contamination by these viruses. These infections are involved in the occurrence of various genital cancers (cancers of the cervix, vulva, vagina, and penis) and cancers of the anus (Suppli et al., 2018). Vaccination against HPV infections aims to reduce the occurrence of precancerous genital lesions in women (and indirectly in men) and ultimately cancers of the cervix, vulva, and vagina in women and cancers of the penis and anus in men (Harper et al., 2006). Because vaccines against papillomavirus infections do not protect against all HPV strains that are involved in CC, vaccination does not replace cervical smear screening. From the age of 25, all women, vaccinated or not, benefit from regular smear screening (Moscicki, 2008). Prophylactic vaccination is an interesting primary preventive measure against CC. Two preventive vaccines against HPV (Gardasil and Cervarix) are widely used. However, the impact of this preventive measure in different

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geographic regions has been associated with the prevalence of genotypes 16 and 18 in different populations (Laurent et al., 2018). Gardasil is a quadrivalent vaccine that uses amorphous aluminum against HPV16 and 18 (which cause 70% of cervical cancerous lesions and 50% of CIN 2 and 3) and HPV6 and 11 (which cause 95% of genital warts) and hydroxyphosphate sulfate as adjuvant. It is particularly indicated for the prevention of CC, precancerous genital lesions (cervical, vulvar, and vaginal) and genital warts associated with HPV 6/11/16/18. Cervarix, a bivalent vaccine against HPV 16 and 18 (Harper et al., 2006), uses aluminum hydroxide as an adjuvant and is able to stabilize virus-like particles (VLPs) and induce antibody levels with lower antigenic mass. Cervarix is used to prevent cervical precancerous lesions associated with HPV 16/18. The vaccination schedule is three doses at 0, 1, and 6 months. The two vaccines that are on the marketed at present have not shown a beneficial therapeutic effect on CIN lesions in women already infected with one of the HPV types included in the vaccine. In fact, VLP-based vaccines were never promised to be therapeutic because the two proteins, L1 and L2, are not abundantly expressed in CIN 2 and 3 (Moscicki, 2008). Mass vaccination would be of particular interest in developing countries, where the incidence of CC is particularly high. Given the effectiveness of previously proposed HPV vaccines and the absence of serious side effects, the effective implementation of vaccination seems simple and obvious. However, significant challenges still need to be addressed. The huge controversy surrounding these anti-HPV vaccines has raised questions about their effectiveness and true side effects. Given the sensitive targets represented by adolescents and the complexity of the disease’s natural history, vaccine targeting may facilitate or conversely slow the availability of HPV vaccination (McLendon et al., 2021).

22.10 Conclusion In conclusion, cancer of the cervix is caused by HPV or human papillomavirus. Among the HPVs, about 15 can cause lesions of the cervix that are likely to give rise to cancer. In addition, HPVs are transmitted from person to person through casual contact during sexual intercourse. This cancer develops in the part of the uterus that opens onto the vagina, that is, the cervix. Disease occurs when cells become abnormal and multiply. Finally, we can say that the proposed means of prevention are effective if they are taken seriously. G G G

Have a cervical smear every 3 years. Get vaccinated before first sexual intercourse. Use condoms.

However, despite publicity campaigns by pharmaceutical companies and governments, young girls remain very poorly informed about CC. Many are

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influenced by antivaccine groups, even when studies have shown the absence of a link between the side effects observed in some young girls and the vaccine. However, through vaccination, we can avoid this cancer, which is the second leading cause of death in women worldwide.

References Ahmad, A., & Ansari, I. A. (2021). A Comprehensive review on cross-talk of human papilloma virus oncoproteins and developmental/self-renewal pathways during the pathogenesis of uterine cervical cancer. Current Molecular Medicine, 21(5), 402
441. Al Moustafa, A.-E., Foulkes, W. D., Benlimame, N., Wong, A., Yen, L., Bergeron, J., & AlaouiJamali, M. A. (2004). E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells. Oncogene, 23(2), 350
358. Available from https://doi.org/10.1038/sj.onc.1207148. Andrew, T., Fru, C. N., Brady, M. R., Cho, F. N., Thierry, T., Paulette, N. F., & Renald11, T. (2021). Knowledge and risk factors of cervical cancer among women in towns of fako division-cameroon. Journal of Advances in Medicine and Medical Research, 33, 81
91. Celegato, M., Messa, L., Bertagnin, C., Mercorelli, B., & Loregian, A. (2022). Targeted disruption of E6/p53 binding exerts broad activity and synergism with paclitaxel and topotecan against HPV-transformed cancer cells. Cancers, 14(1), 193. Chen, L., Liu, S., & Tao, Y. (2020). Regulating tumor suppressor genes: Post-translational modifications. Signal Transduction and Targeted Therapy, 5(1), 1
25. Chen, X., Zhang, P., Chen, S., Zhu, H., Wang, K., Ye, L., & Cheng, X. (2020). Better or worse? The independent prognostic role of HPV-16 or HPV-18 positivity in patients with cervical cancer: A meta-analysis and systematic review. Frontiers in Oncology, 10, 1733. Ciardo, D., Goldar, A., & Marheineke, K. (2019). On the interplay of the DNA replication program and the intra-S phase checkpoint pathway. Genes, 10(2), 94. Cosper, P. F., Bradley, S., Luo, Q., & Kimple, R. J. (2021). Biology of HPV mediated carcinogenesis and tumor progression. Seminars in Radiation Oncology, 31(4), 265
273, WB Saunders. Del Lo, G., Basse´ne, T., & Se´ne, B. (2021). COVID-19 And the african financial markets: Less infection, less economic impact? Finance Research Letters, 45, 102148. Desai, K. T., Befano, B., Xue, Z., Kelly, H., Campos, N. G., Egemen, D., & de Sanjose, S. (2022). The development of “automated visual evaluation” for cervical cancer screening: The promise and challenges in adapting deep-learning for clinical testing. International Journal of Cancer, 150(5), 741
752. Ezebialu, C. U., Ezebialu, I. U., & Ezenyeaku, C. C. (2021). Persistence of cervical human papillomavirus infection among cohort of women in Awka, Nigeria. African Journal of Clinical and Experimental Microbiology, 22(3), 344
351. Ferreira, A. R., Ramalho, A. C., Marques, M., & Ribeiro, D. (2020). The interplay between antiviral signalling and carcinogenesis in human papillomavirus infections. Cancers, 12(3), 646. Giuliani, E., Rollo, F., Dona`, M. G., & Garbuglia, A. R. (2021). Human papillomavirus oral infection: Review of methodological aspects and epidemiology. Pathogens, 10(11), 1411. Gupta, S., Nadaf, A., & Latoo, S.H. (2021). Potentially malignant disorders of the oral cavity. Dentomed Publication House. Harper, D. M., Franco, E. L., Wheeler, C. M., Moscicki, A. B., Romanowski, B., Roteli-Martins, C. M. . . . HPV Vaccine Study group. (2006). Sustained efficacy up to 4  5 years of a

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bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. The Lancet, 367(9518), 1247
1255. Hashim, D., Engesæter, B., Skare, G. B., Castle, P. E., Bjørge, T., Trope´, A., & Nyga˚rd, M. (2020). Real-world data on cervical cancer risk stratification by cytology and HPV genotype to inform the management of HPV-positive women in routine cervical screening. British Journal of Cancer, 122(11), 1715
1723. Heard, I., Tondeur, L., Arowas, L., Falgui_eres, M., Demazoin, M.-C., & Favre, M. (2013). Human Papillomavirus types distribution in organised cervical cancer screening in France. PLoS One, 8, e79372. Hoai, B. N., Cao, T. N., Luong Thi, L. A., Nguyen, M. N., Duong, H. Q., & Than, V. T. (2021). Human papillomavirus prevalence and genotype distribution in Vietnamese male patients between 2016 and 2020. Journal of Medical Virology, 94(6), 2892
2896. Hume, S., Dianov, G. L., & Ramadan, K. (2020). A unified model for the G1/S cell cycle transition. Nucleic Acids Research, 48(22), 12483
12501. Ibragimova, S. (2021). Particuliers de la traduction ukrainienne de la terminologie des brevets d’invention franc¸ais. Advanced Linguistics, 8. Jit, M., Prem, K., Benard, E., & Brisson, M. (2021). From cervical cancer elimination to eradication of vaccine-type human papillomavirus: Feasibility, public health strategies and costeffectiveness. Preventive Medicine, 144, 106354. Lahmamssi, C., Guy, J. B., Benchekroun, N., Bouchbika, Z., Taoufik, N., Jouhadi, H., & Magne´, N. (2020). De´sescalade the´rapeutique dans les cancers de l’oropharynx induit par les HPV: mise au point. Cancer/Radiothe´rapie, 24(3), 258
266. Laurent, J. S., Luckett, R., & Feldman, S. (2018). HPV vaccination and the effects on rates of HPV-related cancers. Current Problems in Cancer, 42(5), 493
506. Li, C., Wu, M., Wang, J., Zhang, S., Zhu, L., Pan, J., & Zhang, W. (2010). A population-based study on the risks of cervical lesion and human papillomavirus infection among women in Beijing, People’s Republic of China. Cancer Epidemiology and Prevention Biomarkers, 19(10), 2655
2664. Liu, X., Dakic, A., Chen, R., Disbrow, G. L., Zhang, Y., Dai, Y., & Schlegel, R. (2008). Cellrestricted immortalization by HPV correlates with telomerase activation and Myc engagement of the hTERT promoter. Journal of Virology, 82(23), 11568
11576. Mantoani, P. T. S., Siqueira, D. R., Jammal, M. P., Murta, E. F. C., & Nomelini, R. S. (2021). Immune response in cervical intraepithelial neoplasms. European Journal of Gynaecological Oncology, 42(5), 973
981. McBride, A. A. (2021). Human papillomaviruses: Diversity, infection and host interactions. Nature Reviews Microbiology, 20(2), 95
108. McLendon, L., Puckett, J., Green, C., James, J., Head, K. J., Yun Lee, H., & Daniel, C. L. (2021). Factors associated with HPV vaccination initiation among United States college students. Human Vaccines & Immunotherapeutics, 17(4), 1033
1043. Mir, B. A., Rahaman, P. F., & Ahmad, A. (2021). Viral load and interaction of HPV oncoprotein E6 and E7 with host cellular markers in the progression of cervical cancer. AIMS Molecular Science, 8(3), 184
192. Moscicki, A. B. (2008). HPV vaccines: Today and in the future. Journal of Adolescent Health, 43(4), S26
S40. Patrick, P. (2020). Test HPV pour le de´pistage du cancer du col ute´rin: La re´ticence des cytopathologistes suisses aux nouvelles recommandations est-elle justifie´e? Forum Medical Switzerland, 20(1718), 303
304.

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Purwanto, D. J., Soedarsono, N., Reuwpassa, J. O., Adisasmita, A. C., Ramli, M., & Djuwita, R. (2020). The prevalence of oral high-risk HPV infection in Indonesian oral squamous cell carcinoma patients. Oral Diseases, 26(1), 72
80. Roskoski, R., Jr (2019). Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs. Pharmacological Research, 139, 471
488. Saldivar, J. C., Hamperl, S., Bocek, M. J., Chung, M., Bass, T. E., Cisneros-Soberanis, F., & Cimprich, K. A. (2018). An intrinsic S/G2 checkpoint enforced by ATR. Science, 361 (6404), 806
810. S´anchez-Camargo, V. A., Romero-Rodr´ıguez, S., & V´azquez-Ramos, J. M. (2021). Noncanonical functions of the E2F/DP pathway with emphasis in plants. Phyton, 90(2), 307. Santacroce, L., Di Cosola, M. D., Bottalico, L., Topi, S., Charitos, I. A., Ballini, A., & Dipalma, G. (2021). Focus on HPV infection and the molecular mechanisms of oral carcinogenesis. Viruses, 13(4), 559. Sitz, J. (2021). De´re´gulation par le virus du papillome humain de l’ubiquitine E3-ligase RNF168 et caracte´risation de son domaine de liaison: le E7BD. The`se de doctorat, Universite´ Laval. Suppli, C. H., Hansen, N. D., Rasmussen, M., Valentiner-Branth, P., Krause, T. G., & Mølbak, K. (2018). Decline in HPV-vaccination uptake in Denmark
the association between HPVrelated media coverage and HPV-vaccination. BMC Public Health, 18(1), 1
8. Turashvili, G., Blay, S., Conner, J., Dickson, B., Demicco, E., & MacMillan, C. (2021). Detection of high-risk human papillomavirus subtypes by RNA in situ hybridization in formalin-fixed paraffin-embedded tissue. Canadian Journal of Pathology, 13(1), 11. Vidal, A., Murphy, S., Hernandez, B., Vasquez, B., Bartlett, J., Oneko, O., Mlay, P., Obure, J., Overcash, F., Smith, J., van der Kolk, M., & Hoyo, C. (2011). Distribution of HPV genotypes in cervical intraepithelial lesions and cervical cancer in Tanzanian women. Infect Agents and Cancer, 6, 20. Walboomers, J. M., Jacobs, M. V., Manos, M. M., Bosch, F. X., Kummer, J. A., Shah, K. V., Snijders, P. J., Peto, J., Meijer, C. J., & Munoz, N. (1999). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. Pathology, 189, 12
19. Wang, X., Wang, G., Zhang, L., Cong, J., Hou, J., & Liu, C. (2018). LncRNA PVT1 promotes the growth of HPV positive and negative cervical squamous cell carcinoma by inhibiting TGF-β1. Cancer Cell International, 18(1), 1
8. Yete, S., D’Souza, W., & Saranath, D. (2018). High-risk human papillomavirus in oral cancer: Clinical implications. Oncology, 94(3), 133
141. Yugawa, T., & Kiyono, T. (2009). Molecular mechanisms of cervical carcinogenesis by highrisk human papillomaviruses: novel functions of E6 and E7 oncoproteins. Reviews in Medical Virology, 19(2), 97
113. Zulaika, G., Nyothach, E., van Eijk, A. M., Obor, D., Mason, L., Wang, D., & Phillips-Howard, P. (2021). Factors associated with the prevalence of HIV, HSV-2, pregnancy, and reported sexual activity among adolescent girls in rural western Kenya: A cross-sectional analysis of baseline data in a cluster randomized controlled trial. PLoS Medicine, 18(9), e1003756.

Chapter 23

In vivo gene therapy with p53 or p21 adenovirus for prostate cancer Rihabe Boussettine, Youssef Ennaji, Najwa Hassou, Hlima Bessi and Moulay Mustapha Ennaji Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco

23.1 Introduction Prostate cancer is an increasingly common pathology, owing to increases in life expectancy, especially in developed countries. Its onset is related mainly to age. Prostate cancer is a real public health problem, It has become the most common cancer and the second most common cause of cancer death in men aged 50 years in developed countries. Around the world, 543,000 new cases are diagnosed each year, and prostate cancer accounts for 200,000 deaths per year, according to the French National Cancer Institute. The incidence of prostate cancer was multiplied by 4 during the period 1978
2000, and the death rate increased by 40% in France (Fournier et al., 2004). In the United States there has been a decrease of 17.6% in specific mortality from prostate cancer since 1993 (Greenlee et al., 2001). The epidemiology of prostate cancer is a good model of the entanglement of genetic (congenital or acquired) and environmental factors (Remontet et al., 2003). In addition to age, which is the main risk factor, several other ethnic, geographical, genetic, and dietary factors have been identified as promoting carcinogenesis in the prostate gland, and it is not strange nowadays to recognize different aspects of prostate cancer in country and ethnic groupings. However, there are currently no clearly identified environmental factors allowing prevention. Likewise, the results of studies of chemoprevention are highly questionable (Thompson et al., 2003). On the other hand, there are family and ethnic predispositions. For example, the brother of an affected Oncogenic Viruses Volume 1. DOI: https://doi.org/10.1016/B978-0-12-824152-3.00010-X Copyright © 2023 Elsevier Inc. All rights reserved.

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subject has a higher risk for prostate cancer (Fournier et al., 2004), and in France mainly Afro-Caribbean populations from sub-Saharan Africa are more at risk (Ravery et al., 2000). The risk for a man of developing prostate cancer is 1 in 8. The incidence of latent forms of prostate cancer appears to be constant throughout the world, but its clinical form varies by countries and ethnicity. The incidence of prostate cancer varies around the world. The highest rates are found in the United States and the Scandinavian countries, and the lowest rates are found in China and other Asian countries (Fournier et al., 2004). Data on prostate cancer in the Maghreb countries, especially in Morocco, are rare. Prostate cancer is characterized by an often late diagnosis, at a stage locally advanced or metastatic and at an advanced age where curative treatment appears to be less beneficial to patients (Ammani et al., 2009, 2016; Fournier et al., 2004; Hsairi et al., 2002; Ravery et al., 2008). Some studies conducted on populations of North African immigrants in Europe (Ferlay et al., 2010; Kamel et al., 2012) showed better presentation of localized prostate cancer at the time of diagnosis and after radical prostatectomy in men of North African origin compared to Caucasian and African-American populations. Changes in the p53 gene (also known as TP53) are among the most common abnormalities in gliomas. Restoration of wild-type p53 is a protein function in prostate cells, resulting in programmed cell death (apoptosis). The functions of p53 are mediated by genes that directly control the tumor suppressor effect of the p53 protein, underlining the relationship between p53 and p53-related genes in prostate cells produced to design more rational treatment strategies for prostate cancer (Gomez-Manzano et al., 1997). Although the anticancer effect of p53 is well documented, the underlying mechanisms and the interrelationships that the differences can generate in the control of programmed cell death (apoptosis) are still under extensive scrutiny. In this regard, the ability of p53 to activate transcription indicates that p53-induced genes may mediate its biological role as a tumor suppressor (Gomez-Manzano et al., 1997). The p53 protein positively regulates (i.e., increases) the expression of at least two genes, p21 and bax, whose encoded products are capable of regulating growth arrest and apoptosis. Together, these data support the idea that p21 participates in the G1 checkpoint mediated by p53 (James et al., 1995).

23.2 Protein P53 23.2.1 History The P53 protein was first discovered in 1979 as a specific antigen of certain chemically induced sarcomas in mice (DeLeo et al., 1979). It was also found

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in cancer cells or transformed by certain viruses (Lane & Crawford, 1979; Linzer et al., 1979) and especially complexed with the large T antigen of SV40 (Harlow et al., 1981; Oren et al., 1981). P53 has also been found in chemically transformed cells and in tumor cells (Crawford et al., 1981). Its expression is also increased in the case of stimulation of the proliferation. At first it was considered to be a proto-oncogene. In 1989, p53 was identified as a tumor suppressor following the observation of loss of activity in many human and murine tumors (Hollstein et al., 1991, 1994; Nigro et al., 1989). The P53 protein is present in all cells of the body, and is activated when a cell undergoes oncogenic or genotoxic stress. It is likely to induce antiproliferative responses, such as stopping its growth, entering senescence, or even its destruction, by activating the transcription of its target genes. It is strongly involved in cell cycle regulation and induction of apoptosis.

23.2.2 P53 a gatekeeper In many human and murine tumors, p53 is mutated or deleted, which alters its function. The first mutations of p53 in humans were revealed in 1989 in colorectal and bronchial cancer cells (Baker et al., 1989; Bodmer et al., 1989; Nigro et al., 1989). Mice that do not express p53, although they were viable, were predisposed to multiple cancers, including sarcomas and lymphomas (Donehower et al., 1992). Constitutional mutations in p53 are at the origin of rare familial Li-Fraumeni syndrome (Srivastava et al., 1990), representing a genetic predisposition for a broad spectrum of cancers, mainly sarcomas, breast cancer, leukemia, and lymphoma, among members of the same family (Malkin et al., 1990). The function of P53 is to ensure and maintain order in cells. It is expressed in all normal cells and is kept inactive. Its level of expression remains low because of its association with the oncoprotein MDM2, which causes its transport from the nucleus to the cytoplasm and its degradation by the ubiquitin-dependent pathway (Momand et al., 1992). The native form of P53 is stabilized and activated when cells are under metabolic or genetic stress, such as hypoxia or activation of oncogenes. Activation of P53 depends on cell type and type of stress and leads to cell cycle inhibition, DNA repair, inhibition of angiogenesis and metastases, differentiation, senescence, induction of apoptosis, and possibly other cellular responses that are currently unknown (May & May, 1999; Vousden, 2002). Cell cycle arrest and induction of apoptosis are the two most studied mechanisms. One of the first molecular functions of p53 is its ability to bind DNA through its central domain. It thus acts as a transcription factor and directly or indirectly regulates the expression many genes in vitro and in vivo. Once it is bound to the GAL4 polypeptide, P53 acts as a transcription activator (Fields & Jang, 1990). This innovative discovery is the basis of the identification of the function major role of P53 in the transcriptional

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regulation of many target genes. A certain number of P53 targets participating in different cellular processes have been identified. Their action determines the fate of cells, cell cycle arrest, or apoptosis. Recent studies have studies show that P53 induces apoptosis directly in the mitochondria.

23.2.3 Structure of the P53 protein The p53 gene is located on the short arm of chromosome 17 at position p13.1. It is composed of 11 exons, the first being noncoding. Its product is an oligomeric phosphoprotein nuclear power of 393 amino acids (Somasundaram, 2000) and a molecular weight of 53 kDa. The expression of P53 is constitutive and ubiquitous, and its functional regulation is essentially posttranslational. Its organization in functional areas is characteristic of that of a transcription factor (Fig. 23.1). The N-terminal region comprises the transactivation domain that is necessary for the function of transcriptional activation of target genes, which are responsible for the interaction of P53 with different factors involved in transcription (TBP, TAF1, and TFIID) (Lu & Levine, 1995), as well as a region that is rich in proline residues, which are necessary for cycle arrest cellular and the induction of apoptosis by P53 (Venot et al., 1998). The central region is required for the specific binding of P53 to DNA. Specific fixation of P53 to DNA is necessary for its oncosuppressive function. It includes the four regions that are preserved (May & May, 1999; de Fromentel et al., 1990). The C-terminal region includes the tetramerization domain, which facilitates binding specific for P53 as well as a basic domain that participates in the downregulation of P53. It is therefore involved in apoptosis, the regulation of transcription, and recognition of DNA damage (Wang & Prives,

FIGURE 23.1 Schematic representation of the three structural domains of the P53 protein. The p53 protein has 393 amino acids. The N-terminal part, made up of the first 100 amino acids, is strongly acidic. This zone contains the transactivation domain as well as the MDM2binding site. The central part consisting of residues 102
292 and forms a structural domain that is capable of specifically binding a DNA sequence. The C-terminal part, positively charged and consisting of amino acids 300
393. This domain contains the tetramerization domain of the protein (residues 324
355), the signals of nuclear localization of P53, and a downregulatory domain of specific DNA-binding activity (residues 368
393). Residues 316
324, 370
376, and 380
386 correspond to a nuclear localization sequence. Residues 11
24 and 340
351 correspond to nuclear export sequences. The p53 protein has five highly conserved regions (I, II, III, IV, and V).

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1995; Wang et al., 1996). The presence of three nuclear localization sequences at the level of the C-terminal region and nuclear export signals to the cytoplasm allow the regulation of subcellular localization of P53 (Dang & Lee, 1989).

23.2.4 Regulation of P53 In stressed cells, P53 is overexpressed and can lead to cell cycle arrest or induction of apoptosis, depending on cell type, extracellular signals, and/or P53 expression level. P53 is highly regulated at the posttranslational level by covalent modifications. Posttranslational modifications of P53 include phosphorylation, acetylation, ubiquitination, glycosylation, and sumoylation (Fig. 23.2).

23.2.4.1 Phosphorylation of P53 Phosphorylation of P53 can be ensured by numerous kinases (ATM, ATR, CDK1, CHK1 1 , CHK2 1 , DNA-PK, P38, etc.) (Bischoff et al., 1990; Hall

FIGURE 23.2 Posttranslational modifications at the level of the different domains of P53. Schematic representation of the p53 protein and the specific residues that are subject to posttranslational modifications. The location of the posttranslational modification sites is indicated. The numbers are relate to amino acid residues. S: serine; K: lysine.

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et al., 1996; Woo et al., 1998) (Fig. 23.3). This change has the effect of increasing the efficiency of P53 as a transcription factor by increasing its affinity for gene-encoding proteins, such as Bax or P21, which control apoptosis and the cell cycle, respectively, and stabilize the P53 protein by preventing its ubiquitination by MDM2.

23.2.4.2 Acetylation of P53 DNA damage induces phosphorylation of P53 on the N-terminal, promoting its association with proteins of the histone acetyltransferase p300/CREBbinding protein (CBP) type, which will increase its acetylation and its activity (Barlev et al., 2001; Lambert et al., 1998; Sakaguchi et al., 1998). Acetylation increases the affinity of P53 to DNA. Other modifications may regulate the activity of P53, including methylation by methyltransferases such as Set9 (Chuikov et al., 2004). Set9 methyl P53 at the level of lysine 372 residue stabilizes and activates P53 and confines it at the level of the nucleus, which leads to induction of apoptosis. 23.2.4.3 Ubiquitination of P53 P53 can be ubiquitinated, resulting in its translocation from the nucleus to the cytoplasm and its degradation via the proteasome. 23.2.4.4 Other Modifications of P53 P53 can also be sumoylated, ribosylated, neddylated, and O-glycosylated. 23.2.4.5 Interaction of P53
MDM2 MDM2 plays a central role in the regulation of P53. MDM2 has been shown to bind specifically to the N-terminus (residues 17
27) of P53, a part that contains different phosphorylation sites. This interaction blocks the transactivation domain of P53, inhibits its transcriptional activity, and induces its

FIGURE 23.3 Regulation of P53 by MDM2. MDM2 regulates P53 through three different pathways.

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degradation (Chen et al., 1993; Oliner et al., 1993). MDM2 is an E3 ligase that is required for the ubiquitination of its substrates. MDM2 binds to the P53 protein in the nucleus and displaces it in the cytoplasm, or it will be degraded by the proteasome (Gottifredi & Prives, 2001) (Fig. 23.3). The promoter of the MDM2 gene contains a binding domain for the P53 protein, and it is transcribed in a P53-dependent manner (Barak et al., 1993; Perry et al., 1993). However, a high level of MDM2 expression due to high P53 activity generates a self-regulation loop, which enables a rapid turnover in order to regain a normal level of expression of P53 in cells (Haupt et al., 1997; Kubbutat et al., 1997). MDM2 binds to the transactivation domain of P53 and inhibits its transcriptional activity, increases the degradation of P53, and promotes the export of P53 to the nucleus. In the presence of MDM2, P53 is inactive and can no longer stimulate the expression of genes involved in apoptosis, cell cycle arrest, and DNA repair. In tumors that overexpress MDM2, P53 is constitutively inhibited, and tumor growth is favored. Inactivation of MDM2 in these tumors activates P53 and induces apoptosis.

23.2.5 Cellular localization P53 import-export is an active process. Nuclear localization of P53 is required for its regulatory function of transcription. P53 contains three nuclear localization sequences, which transport it to the nucleus after activation. The nuclear export of P53 is due to two nuclear export sequences (O’Brate & Giannakakou, 2003). Transportation nuclear P53 requires the ubiquitin ligase function of MDM2 (Boyd et al., 2000; Yu et al., 2000). The nuclear export of P53 is necessary for its degradation (Freedman & Levine, 1998). Other proteins directly or indirectly regulate import-export nuclear P53, such as PI3K, P14ARF, actin, mot2, vimentin, and importin (O’Brate & Giannakakou, 2003).

23.2.6 The functions of P53 The P53 protein is localized in the cytoplasm. Under normal conditions, it is moves from the cytoplasm to the nucleus during the G1/S transition and remains there until the G2 phase. The cell cycle is regulated by several proteins, such as cyclin-dependent kinases cyclins (CDKs) and CDK inhibitors. The normal succession of different phases of the cell cycle is controlled by checkpoints that block the progression of the cell cycle in the event that cells suffer DNA damage. P53 activates the control points in G1/S and G2/M phases following physiological stress.

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23.3 Cell cycle arrest 23.3.1 Cell cycle arrest in the G1 phase P21, is a gene that induces cell cycle inhibition by P53 at G1 and G2 by inhibiting cyclin E/CDK2 and cyclin B/CDK1 complexes, respectively (Agarwal et al., 1995; Bunz et al., 1998; Kastan et al., 1991). CDK1 (also called CDC2) is necessary for the entry of cells into mitosis (Azzam et al., 1997). It is inhibited by P21. P21 is also involved in the signaling pathway of RB tumor suppressor. The RB protein is inactivated by cyclin hyperphosphorylation/CDKs during the succession of the different stages of the cell cycle. Induction of p21 causes inhibition of cyclin E/CDK2, causing hypophosphorylation of RB. The latter binds to E2F and inhibits transcription of cell cycle genes that are controlled by E2F (Stewart et al., 2001).

23.3.2 Cell cycle arrest in the G2 phase P53 and its target genes are not only involved in cycle arrest in the G1 phase but seem to be involved in all checkpoints of the cell cycle. Several recent studies have shown that the arrest of the cell cycle in the G2 phase after onset of genotoxic damage is truly P53 dependent. The key factor for this G2/M transition is the CDK1
cyclin B1 complex. This cytoplasmic complex does not fit in the nucleus only at the time of mitosis. The 14-3-3 gene, transactivated by P53, is capable of sequestering this CDK1
cyclin B1 complex in the cytoplasm to cause cell division in the G2 phase. Cells in which the two copies of the 14-3-3 gene have been inactivated are no longer able to induce this arrest of cell division. Irradiation of these cells induces abnormal mitosis, which leads to their death by mechanisms that are not apoptotic. A second P53 transactivated gene, GADD45A, is also important for the control of the G2/M transition. Inactivation of this gene in mice leads to a very similar to that of p53 (2/ 2 ) mice. The cells of these GADD45A (2/ 2 ) mice show a strong aneuploidy and many chromosomal abnormalities and are no longer able to stop in the G2 phase in response to stress induced by irradiation.

23.3.2.1 Apoptosis The role of the P53 protein is not as clear in apoptosis as it is in cell cycle arrest. This is due to the heterogeneity of this apoptotic function. There could be two ways, one through the transactivation activity of the protein and the other using a mechanism independent of transcription. For the transcriptiondependent pathway, several genes have been identified. These are Bax, IGFBP3, and PIG3. The mechanisms of apoptosis-independent transcription, induced by P53, are not known. These could involve protein-protein interactions. The 53BP2 protein, which competitively interacts with P53 and Bcl2,

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is a good candidate. It is also interesting to note that low amounts of P53 are able to protect cells from apoptosis.

23.3.2.2 Extracellular signaling The initiators of the extracellular signaling pathway are the transmembrane receptors and their respective ligands. The formation of DISC including receptor ligand, adapter molecules, and caspase 8 activate effector caspases. Fas or CD95 cell receptors are keys to the induction of its signaling pathways, which are activated by the binding of the ligand, FasL. Fas is a target of P53; it is transcriptionally activated as a result of induced DNA damage (Mu¨ller et al., 1998). The death domain that contains the Dr5/KILLER receptor of the TRAIL family is also a target of P53 in cells that have suffered damage to the apoptosis-inducing DNA level in different tissues (Burns et al., 2001; Wu et al., 1997). The third transmembrane protein that is induced by P53 in response to DNA damage is PERP, which induces apoptosis, probably in collaboration with E2F1 (Attardi et al., 2000).

23.4 Protein P21 Cyclin-dependent kinase inhibitor 1, also known as CDK-interaction protein 1 or more simply as p21, is a cell cycle inhibitor that introduced inhibition of CDK/cyclin as well as arrest of cycle during the G1/S phase. In humans, p21 is encoded by the CDKN1A gene on chromosome 6 (Abbas & Bassam, 2009). Studies have explained the use of p21 as the target of p53 activity and have implicated it in the regulation of cell cycle, apoptosis, and transcription. Therefore studying p21 can help to uncover cell processes after DNA events (Karimian et al., 2016). Prolonged research has begun to establish a body of knowledge about the indispensable roles of p21 expression and activity in relation to the establishment and development of cancer. For this reason, the future of p21 research is likely to be a direction in oncology, in exploring potential developments based on our growing knowledge about p21 (Montero, 2019).

23.4.1 P21 and cancer All of the roles of p21 in cell function are linked to its cancer mediation. This is because p21 governs, at least in part, all of the vital cellular functions, which are in the establishment, progression, and therapeutic response of cancer cells (Abbas & Dutta, 2009; Shamloo & Usluer, 2019). Since p21 has been implicated in cell cycle arrest, it is predictable that scientists have been exploiting its function to treat cancer (Fig. 23.4). Some chemotherapeutic agents have been designed to induce p21 activity to have the effect of preventing cancer progression (Karimian et al., 2016).

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FIGURE 23.4 The molecular basis of p21 function in cancer (Abbas & Dutta, 2009). The figure shows activities of p21 in the nucleus and cytoplasm. (A) Under certain conditions, p21 promotes the kinase activity of cyclin-dependent kinase 4 (CDK4) or CDK6 in complex with cyclin D, thus promoting progression through G1 (Labaer et al., 1997). p21 inhibits CDK2
cyclin E, with the consequent inhibition of CDK2-dependent phosphorylation of RB and the sequestration of E2F1, thus inhibiting E2F1-dependent gene transcription and progression into and through the S phase. p21 also inhibits the kinase activity of CDK2
cyclin A and CDK1
cyclin A, which are required for progression through the S phase and into the G2 phase, respectively. Additionally, p21 inhibits the kinase activity of CDK1
cyclin B1, thus inhibiting progression through G2 and G2/M. (B) Through its carboxyl-terminal domain, p21 binds to and inhibits proliferative cell nuclear antigen (PCNA), thereby inhibiting processive DNA synthesis and modulating PCNA-dependent DNA repair pathways. (C) p21 can inhibit the transcriptional activity of the transcription factors E2F1, STAT3 (signal transducer and activator of transcription 3) and MYC through direct binding and inhibition of their transactivation activity. This accounts for some of the antiapoptotic effects of p21, which may contribute to its oncogenic activity. (D) p21 phosphorylation at Thr145 by activated AKT1 (also known as PKB) downstream of ERBB2 (a member of the epidermal growth factor receptor family of receptor tyrosine kinases) or IKKβ (inhibitor of nuclear factor-κB kinase-β) signaling prevents the nuclear translocation of p21 (Ping et al., 2006; Winters et al., 2003; Zhou et al., 2001). Cytoplasmic p21 exhibits antiapoptotic activity, owing to the inhibition of proteins that are involved in apoptosis. Whether the phosphorylation of p21 by AKT1 functions only to retain p21 in the cytoplasm or is also required for its cytoplasmic activities is not clear. ASK1, apoptosis signal-regulating kinase 1, also known as MAP3K5; SAPK, stress-activated protein kinase.

P21 exerts a triggering effect on CDK2 activity, which, in turn, prevents cell cycle progression. By activating p21 and generating CDK2, the researchers identified the therapeutic possibility of targeting p21 to prevent the proliferation of cancer cells (Abbas & Dutta, 2009). Breast cancer, in particular, has been linked with the shock of p21 on the regulation of gene transcription. Expression of the estrogen receptor-

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α-dependent (ERα) gene is assisted, at least in part, by transcription of the p300-CREBBP-driven genes, which is activated by p21 (Karimian et al., 2016). Differentiation of ERα-positive cells is mediated by this activity, and for this reason, upregulation of p21 may prevent the growth of ERα-positive breast cancer cells. This discovery has alerted scientists to the shock that p21 can have on the effectiveness of antiestrogen treatments (Montero, 2019). A hallmark of cancer is its intense ability to prevent apoptosis, allowing cancer cells to thrive in spite of the body’s efforts to begin regulated cell death processes (Montero, 2019). P21 has been considered both an aid and an obstacle in the progression of cancer. On the one hand, it has been targeted to stimulate cell cycle arrest to prevent the progression of cancer; on the other hand, it has been linked to inhibiting apoptosis, a condition that allows cancer to thrive. P21 can protect cells against apoptosis by promoting cell cycle inhibition, and cells that are not active are less likely to trigger apoptosis (Karimian et al., 2016). Conversely, the role of p21 in DNA repair gives it a useful role in preventing cancer progression. Since p21 prevents cell cycle progression as well as apoptosis, DNA repair can take place during this cycle pause. DNA repair is essential for protection against cancer; therefore p21 may contribute to tumor-suppressing activities, although more research is needed to confirm this (Shamloo & Usluer, 2019).

23.5 Adenovirus 23.5.1 Nomenclature Of all the genetically modified viruses, adenoviruses are by far the most widely studied. The use of adenoviruses as a cancer treatment dates back to the 1950s. During this period, Rowe first isolated a virus that was later called adenovirus from tonsil and adenoids biopsies. This undisclosed doublestranded DNA virus contains an icosahedral capsid and belongs to the Adenoviridae family. This family now includes five generations found within the five main classes of the genus Mastadenoviruses, which infect humans, includes seven subgroups (A to G), subdivided into 57 serotypes (Reddy et al., 2006; Sharma et al., 2009; Tong et al., 2010; Walsh et al., 2011), which are classified according to biochemical, biological and pathological criteria. All the serotypes that are present within the same adenoviral subgroup show strong sequence homologies ( . 70%), indicating a very strong conservation during evolution. These adenoviral serotypes are classified and defined by their ability to be neutralized by a specific antiserum. This neutralization process occurs through the binding of antibodies to adenoviral capsid proteins, such as hexon and fiber (Toogood et al., 1992). In addition, the serotypes are ordered according to four hemagglutination profiles according to their ability to agglutinate erythrocytes of different species. Indeed,

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one distinguishes those causing a complete agglutination of the erythrocytes of monkey (I) or rat (II) from those causing only partial (III) or no (IV) agglutination of rat erythrocytes. Most adenoviral serotypes are not oncogenic in humans. They can nonetheless induce mild infections in an immunocompetent individual, such as pharyngitis, conjunctivitis, tracheobronchitis, or even bronchopneumopathy and mesenteric adenitis (Zhang et al., 2005). In contrast, in immunocompromised subjects or in children, adenoviruses can cause more complications, including severe pneumonia, which can lead to death. These different adenoviral serotypes are capable of preferentially infecting tissues. For example the adenoviruses of subgroups B, C, and E infect the respiratory tract, those of subgroup D infect the ocular system, and those of subgroups F and G infect the gastrointestinal system. To use adenoviruses in human therapy, it is therefore essential to select low-pathogenic serotypes and take into account the viral tropism.

23.5.2 Structure of adenovirus Adenoviruses are 28- to 48-kb, nonenveloped, linear, double-stranded DNA viruses with an icosahedral capsid whose 20 triangular faces form 12 vertices. These viruses have a size of the order of 70
100 nm and consist of an outer capsid that surrounds the core (also called the viral nucleoid). The core of adenoviruses consists of viral DNA but also proteins of structure V, VII, and X (or μ) (Lo´pez-Campos et al., 2007) and a protein terminal (Tp) located at each 5’ end of the genome which initiates virus replication at the origins of replication (inversed terminal repeat, or ITR). This core also has a viral protease that is essential for the maturation of virions (Russell, 2000). In addition, there are in region 50 of the adenoviral genome an encapsidation sequence (psi, Ψ) allowing the virus to encapsidate its genome (Russell, 2000) (Fig. 23.5). The absence of an envelope explains why adenoviruses are resistant to lipid solvents and to changes in temperature or pH.

23.5.3 Attachment and entry of the virus into the host cell The entry of the virus into the host cell is the first stage of the viral cycle. This entry takes place in two stages. A first step is for the adenovirus to attach itself to the cell surface (Fig. 23.6). For the adenovirus of subgroup C this attachment is mediated by the interaction of the head of the fiber with the primary coxsackievirus and adenovirus receptor (CAR) (Patzke et al., 2010; Tamanini et al., 2006). The second step necessary for the entry of the virus is the bonding of the RGD peptide motif, which is present in the outer loop of the base of the penton with cellular integrins (αv β1, αv β3, αv β5, α3 β1, and α5 β1) (Lyle & McCormick, 2010). Recruitment integrins then activate the endocytosis of virions, mainly through vesicles to the clathrin mantle

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Fiber Penton base Protease

Protein VI Hexon protein Protein XI

Core proteins (V, VII and P)

Terminal protein

T=25 FIGURE 23.5 Structure of adenovirus. Viral DNA as well as the main capsid proteins (base of penton, hexon, fiber, protein IX) and the adenoviral core (protease, Tp, V, VII, and μ proteins) are represented (http://viralzone.expasy.org/all_by_species/183.html).

(Mercer et al., 2010). It has been shown that a KKTK pattern (Lys-Lys-Thr-δys residue), present in the stalk of the fiber, allows attachment and entry of adenovirus into cells as a result of interaction with glycosaminoglycan-type heparan sulfates, which are almost ubiquitously expressed on the surface of cells. Then the process of endocytosis brings the virus inside the cell, in the endosomes (Tsai, 2007). The acidity that is present in the endosomes induces the disassembly of the minor proteins that are responsible for stabilizing the capsid and cause the undressing of the latter (Greber et al., 1993). The acidity of the endosomes, the binding of the penton base to cellular integrins, and the presence of viral proteins in solution cause the adenovirus to escape from the endosomes into the cytoplasm (Maier et al., 2012). Once it is in the cytoplasm, hexon proteins will recruit microtubule motor proteins, known as dyneins, and transport what remains of the viral capsid to the cell nucleus in the vicinity of nuclear pores (Bremner et al., 2009). The complete disappearance of the viral capsid occurs at the level of these nuclear pores, and the viral DNA is translocated into the nucleus through nuclear import pathways using chaperone proteins, in particular HSP70 (heat shock protein). Thu, through these chaperone proteins and the nucleoporin CAN/Nupβ14, viral DNA associated with Tp, V, and VII proteins crosses the nuclear membrane and is taken up by cellular histone H1 and associated import factors. The process from virus attachment to the cell surface to genome import into the nucleus takes between 0 and 60 minutes, depending on the cell type (Fig. 23.6).

23.5.4 Early gene transcription The various early genes (E1A, E1B, E2, E3, and E4) are transcribed and translated during entry of the viral genome into the nucleus before

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FIGURE 23.6 Infection of epithelial cells with Ad subgroup C (Coughlan et al., 2010). The fiber interacts with the CAR receptor, followed by αv integrins, leading to endocytosis via the clathrin-mantle vesicles. The adenovirus then ends up in the endosomes. The acidification in these will cause stripping of the viral capsid and activation of protein VI, triggering the escape of the virus into the cytoplasm. The proteins dynein/dynactin recruited by the hexon then transport the rest of the viral particle along the microtubules to the nucleus. The virus eventually attaches itself to the nuclear pore complexes formed by CAN/Nupβ14 and disassembles by recruiting H1 nuclear histone and its import factors (importin ȕ and 7).

replication begins. Their function is to implement an environment that is conducive to virus replication by modulating the expression of viral and cellular genes. The E1A gene is the first to be expressed, just after the virus enters the nucleus. This gene undergoes alternative splicing and produce five messenger RNAs: 13S, 12S, 11S, 10S, and 9S. These different transcripts encode respective proteins made up of a number of residues (R): 289R, 243R, 217R, 171R, and 55R (Fig. 23.7) (Flinterman et al., 2007). From proteins of the E1A gene, the 289R and 243R proteins have the most important functions. On the one hand, they activate the promoters of other viral genes in the region early (E1B, E2, E3, and E4) so that they can start their

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transcription. On the other hand, they regulate the transcription of certain cellular genes to produce an environment that is favorable to viral replication by forcing cells to enter the S phase. The 289R proteins and β4γR of E1A consist of four domains, namely, CR1, CRβ, CRγ, and CR4, which are very conserved between different adenoviruses (Avvakumov et al., 2004). E1A proteins, by their domains CR1 and CR2, will cause cells to enter the S phase. The CR1 domain first interacts with the CBP/p300 protein to inhibit it (Ferreon et al., 2009). CBP/p300 is a transcriptional coactivator that is considered as a gene tumor suppressor. CBP/p300 can acetylate the p53 gene via its histone acetyltransferase domain and can induce chromatin decompaction and p53 protein expression, which causes blockage of the cell cycle and even apoptosis of the cell. The activity caused by this DNA breakdown results in the expression of genes involved in cell differentiation and allows maintenance in the G0 phase. However, proteins 289R and 243R are able to block the CBP/p300 protein, which then cannot play its role as a p5γ activator. The cell then loses the ability to control its proliferation and therefore cannot avoid the transition to the S phase (Berk, 2005). The CR2 domain of the E1A 289R and 243R proteins also participates in the passage of the cell into the S phase by interacting directly with the protein of the retinoblastoma gene (pRb) which is a tumor suppressor gene. The

FIGURE 23.7 Isoforms of the E1A region (Flinterman et al., 2007). (A) The different mRNAs derived from the E1A gene are shown. The black rectangles indicate coding regions. This white rectangle corresponds to a coding sequence of E1A 9S, located in a reading frame other than the coding sequences represented by the black rectangles. (B) The respective proteins of the different mRNAs of the E1A region are shown. The number of amino acid residues (R) as well as the position of the different conserved regions (CR1, CR2, CR3, and CR4) are specified.

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pRb protein, in association with homologous proteins such as p107 and p130, is able to regulate the passage of the cell to the S phase by binding the E2F transcription factor, which is then inactive. The EβF factor can bind to DNA and allow the transcription of genes involved in cell division, such as the cyclin E gene. The activity of this factor is regulated by the state of phosphorylation of pRb; thus, when the pRb protein is phosphorylated by the cyclin D/CDK4 complex, it is found in an inactivated state and releases factor E2F, allowing cells to enter the S phase. Conversely, when pRb is dephosphorylated, it sequesters EβF, preventing it from activating genes involved in S phase entry. When infected with an adenovirus, the E1A β89R proteins and 243R, through their CR2 domains, interact with pRb and cause the release of E2F transcription in a transcriptionally active form (Fig. 23.8), forcing the transition from the G1 phase to the S phase of the cell cycle (Berk, 2005; Liu et al., 2007). At the same time, the loss of pRb function induces expression of the tumor suppressor protein p14/ARF, which prevents ubiquitin ligase εDεβ from acting on p5γ, leading to its stabilization. The second gene to be transcribed and expressed is E1B. This gene codes for the two proteins E1B-55kDa and E1B-19kDa (E1B-55K and E1B-19K), both of which have an antiapoptotic role (Miller et al., 2009). Indeed, E1B55K is able to repress the p5γ protein and prevent its accumulation within cells. For this, the E1B-55K protein interacts directly with the p53 protein and masks its DNA-binding domain so that it can no longer act as a transcription factor. E1B-55K directly binds and represses the transactivation domain p53 protein. E1B-55K protein also has the ability to activate cellular factors that will target the cyclin E promoter and increase its expression (Zheng et al., 2008). Cyclin E induction allows formation of the CDK2
cyclin E complex, which is required for entry into the S phase. Adenoviral infection causes an increase in the expression of Bax and Bak proapoptotic proteins. These form a homodimer that binds to the membrane mitochondria and causes the release of cytochrome c, triggering after binding to the caspase 9, activation of the apoptosome (Dewson et al., 2009). The viral protein E1B-19K is synthesized to inhibit apoptosis by a mechanism similar to that of the human protein Bcl-2. Indeed, E1B-19K can bind to Bax and Bak to prevent their homodimerization and avoid the release of cytochrome c, leading to apoptosis (Piya et al., 2011; Sundararajan et al., 2001) (Fig. 23.7). The E1B-19K protein is also capable, by inhibiting Bax, of preventing apoptosis induced by tumor necrosis factor alpha (TNF-α) via the death receptor pathway, in particular by blocking the activation of caspase-3 downstream of caspase-8 (Perez & White, 2000). The second gene region to be expressed is the E2 region. Proteins from the gene E2 are required for viral replication. This region is divided into two subregions: the region EβA, which allows the synthesis of the DNA-binding

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FIGURE 23.8 Representation of the interactions between the cell cycle and early viral proteins (Wong et al., 2010). The diagram shows how early viral proteins neutralize cell cycle regulatory proteins such as pRb or p53 to force the passage of cells into the S phase and thus allow viral replication. The black arrows indicate activating action; the red lines indicate inhibiting action. The retinoblastoma (pRb) protein is normally hypophosphorylated and binds to the transcription factor E2F to prevent passage of cells into the S phase. The appearance of mitogenic signals induces the expression of cyclins, which associate with cyclin-dependent kinases (CDKs). Cyclin D
CDK4/6 or cyclin E/CDK2 complexes phosphorylate pRb, releasing EβF, which leads to the expression of genes involved in S phase progression of the cell cycle. In addition, the release of factor E2F causes overexpression of p14ARF, which inhibits Mdm2. Mdm2 can then no longer degrade the p53 protein, which is then stabilized (usually after a viral infection or DNA damage). The activated p53 protein then induces apoptosis via induction of Bax, cell cycle arrest via p21 (inhibiting CDKβ), or DNA repair. The p16INK4A protein also works by inhibiting CDK4/ 6 proteins. To counteract the effects of pRb and p53, different viral proteins are involved. The E1A protein binds to pRb and allows the release of EβF. Another protein, E1B-55K, induces the expression of cyclin E but interacts also with E4orf6 to ubiquitinylate p53 and causes its degradation via the proteasome. This complex allows inhibition of the export of cellular mRNAs and facilitates the export of late viral mRNAs. Finally, the E1B-19K protein inhibits Bax and prevents the induction of apoptosis.

protein (DBP) associating with viral single-stranded DNA, and the EβB region, which will produce the Tp protein (terminal protein) as well as viral DNA polymerase. The Tp protein is present at each end of the genome to protect it from degradation of exonucleases. The transcription of the Eγ region induces the expression of proteins, the main purpose of which is to modulate the immune system. First, the E3gp19kDa protein binds to the major histocompatibility complex I to prevent its transport to the cell surface and therefore avoid the presentation of viral antigens, which are capable of inducing the activation of T cells directed against the adenovirus (McSharry et al., 2008; Menz et al., 2008). After the infection of certain cells with adenovirus, a large amount of TNF-α is synthesized and triggers an antiviral response that will promote

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inflammation phenomena and of apoptosis. The Eγ region therefore synthesizes proteins to counteract the effects of TNF-α. The E3 10.4-kDa and E3 14.5-kDa proteins form a heterodimer called the E3-RID (receptor internalization and degradation) complex. This RID complex as well as another E3 14.7-kDa protein inhibits inflammation caused by TNF-α by inactivating phospholipase A2, which is responsible for the release of arachidonic acid from phospholipid membranes and indirectly inhibits the release of inflammatory agents such as prostaglandins and leukotrienes. This RID complex also inhibits apoptosis induced by ligands for TNF-α and Fasδ by reducing the expression of death receptors on the surface of cells, such as the TNFR-1 receptor or the Fas receptor. The E3 14.7-kDa protein also prevents apoptosis by interacting with and inhibiting caspase-8 (Chin and Horwitz, 2006; Delgado-Lopez & Horwitz, 2006; Fessler et al., 2004). In this way, the FasL and TNF-α ligands cannot bind to their respective receptors, which blocks the induction of apoptosis. Through elsewhere, the E3 region also codes for the adenovirus death protein, which plays an important role in cell lysis and virion release (Doronin et al., 2003; Subramanian et al., 2006). Finally, the E4 region of the adenovirus appears as a region with multiple functions, including stopping protein synthesis in the host cell, inhibiting p5γ-dependent apoptosis, and facilitating the export of viral messengers to the cytoplasm. One of the genes that is encoded by E4 causes the synthesis of the protein E4orf6. This forms a complex with the protein E1B-55K (E1B-55K/E4orf6), which acts on p53 by blocking its accumulation at the cells, thus preventing apoptosis. Specifically, the E1B-55K/E4orf6 complex acts as a ubiquitin ligase that ubiquitinylates p53 and causes its degradation via the proteasome. E1B55K/E4orf6 is also able to act on the εRN complex (εRE11/Rad50/Nbs1) by inhibiting the MRE11 protein (Carson et al., 2009; Mathew & Bridge, 2007; Rajecki et al., 2009). Recently, adenovirus has been shown to regulate the εRN complex via the sumoylation of MRE11 and Nbs1 (Sohn & Hearing, 2012). After adenoviral infection, double-stranded DNA from the virus is mistaken for a double strand break in DNA by the εRN complex that is involved in recognition of lesions. Activation of this complex results in a blockage of the cell cycle induced by the activation of checkpoints such as the p5γ protein; δ inhibition of the MRE11 protein prevents the εRN complex from detecting the viral genome and generating p5γ protein expression and apoptosis. In addition, the E1B-55K/E4orf6 complex participates in the synthesis of late viral proteins in many cell types, promoting, the nucleocytoplasmic export of viral messenger RNAs while inhibiting the export of cellular messengers (Berk, 2005; Harada et al., 2002). Finally, another protein from this region. E4 called E4orf4 induces cell death independently of the p53 protein via a mechanism different from caspases. In particular, E4orf4 induces arrest in Gβ/ε and cell death in blocking the B55 subunit of serine threonine phosphatase PP2A (Miron et al., 2009). E4orf4 also plays a role in the control of

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alternative splicing of late L1 viral transcripts (Fig. 23.8) (Miron et al., 2009).

23.5.5 Genome replication The start of viral replication first requires the entry of cells into the S phase and a certain level of expression of the proteins that are encoded by the Eβ region of the virus. δ DNA viral polymerase initiates replication at the level of the two ITRs located at the ends of the viral genome that contain the origins of replication. Viral replication involves, on the one hand, the viral protein Tp, which is attached to covalently to ITRs and serves as a primer, and on the other hand, the three transcription factors nuclear NFI, NFII (type I topoisomerase), and NFIII, which ensure the elongation phase of the replication. This phase involves the viral DBP, whose role is to destabilize doublestranded viral DNA by attaching to single-stranded DNA and thus allow the displacement of DNA polymerase on single-stranded DNA in order to replicate it (Mysiak et al., 2004).

23.6 In vivo gene therapy with P53 or P21 adenovirus for prostate cancer Cancer is the end result of genetic alterations in key regulatory molecules, resulting in unregulated cell growth. p53 is a tumor suppressor gene that is mutated in a wide variety of human malignancies (James et al., 1995). Tumors carrying p53 mutations are resistant to treatment with radiotherapy and chemotherapy, and restoration of wild-type (wt) p53 function may lead to reduced tumor expansion and may make tumors sensitive to radiation or cytostatic compounds (Boulay et al., 2000). The introduction of p53 by viralmediated delivery can suppress growth in a number of human cancer cell cells in vitro and in vivo. Adenovirus-mediated gene transfer has been shown in a mouse model for prostate cancer. A study by James et al. in 1995 found that administration of adenovirus p21 can prolong mouse survival and shrink tumor size. In addition, p21 was more effective than p53 in suppressing the growth of tumor cells, suggesting that CDK inhibitors may prove beneficial in the treatment of prostate cancer and possibly other cancers. The cell line that was used in the study has variable susceptibility to adenoviral infection (James et al., 1995). The work of Alonso-Magdalena et al. in 2012 showed that the basal expression of p21 seems to be an important factor in the identification of cells that are sensitive to the cytotoxicity of adenoviruses and to be correlated with the expression of E1A, the in vitro death of malignant and transformed cells, and antitumor activity in vivo. The research also showed that p21 is predominantly cytosolic and is targeted for destruction of the proteasome after infection. Reversal of p21 in high-expressing cells reduces E1A

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expression and adenovirus activity, while reexpression in p21- low cells increased E1A expression and cytotoxicity of dl922
947 and wild-type adenovirus. p21 stabilizes the expression of cyclin D and thus promotes a cellular environment that is conducive to the replication of adenoviruses (AlonsoMagdalena et al., 2012). p53 and p21 are two growth suppressors that are not necessarily composed identically in every type of tumor cell. p21 may be more potent in certain cell types or under certain experimental conditions. James et al. explained that in transcription of p21 the level of p21 that is produced via p53-mediated transcription may not be as high as that obtainable by adenovirus-mediated transduction, owing to differences in promoter strength or efficacy in translation of endogenous and exogenous p21 mRNAs (James et al., 1995). Further studies have shown that p21 under normal diploid fibroblast conditions is associated with active CDK complexes, and it is currently believed that multiple p21 molecules (probably two) are required to inhibit a single CDK. Therefore the growth suppressor of p2l function critically depends on the relative levels of p2l and G1CDK. It is possible that in the prostate tumor cell line that was used, amplified levels of cyclins G1 were present, which would increase the level of p21 required for complete cell cycle arrest. It should be noted that cyclin overexpression is a common feature of various tumors (Sherre et al., 1995) and should be taken into account in designing antitumor therapies. While p21 may have more suppression of growth activity in some systems, there may be benefits to using p53 in gene therapy protocols in some situations. The studies that were launched by Boulay et al. (2000) showed that the expression of the target gene p53 p21 was significantly increased after gene therapy mediated by rAd-p53, indicating the effectiveness of the rAd-p53 delivery process and functionality of the transgenic product and therefore providing evidence for the restoration of the subsequent cycle mediated by p53 arrest in suppressed tumors. The P53 gene is used as a means to fight other types of cancer. Del Valle et al. developed a modified nonreplicating adenoviral vector for gene transfer, called AdRGD-PG, which offers improved transduction and transgene expression. The p53-sensitive PG promoter was used to drive the expression of p53 or human interferon beta (hIFNβ) in human colorectal cancer cell lines HCT116wt (wtp53), HCT116 (2/ 2 ) (p53 deficient), and HT29 (mutant p53). Both HCT116 cell lines were easily killed by p53 gene transfer, while p53 and hIFNβ combined cooperated for the induction of HT29 cell death and the release of immunogenic cell death markers. High annexin V staining and 3/7 caspase activity indicate cell death by a mechanism that is compatible with apoptosis. The transfer of the P53 gene alone or in combination with hIFNβ sensitized all cell lines to chemotherapy, allowing the application of low doses of drug while obtaining a significant loss of viability. While endogenous p53 status was not sufficient to predict response to

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treatment, combined p53 and hIFNβ provided an additive effect in HT29 cells. We propose that this approach may prove to be effective for the treatment of colorectal cancer, allowing the use of limited drug doses (Del Valle et al., 2021).

23.7 Conclusion Cancer treatments have continuously evolved in parallel with our biological and molecular understanding of this pathology. The same goes for innovative therapies, in particular gene therapies, which require regulations and guidelines to allow the best efficacy and safety when used in humans. The design of a gene therapy product varies according to the choice of genetic material involved, the presence or absence of a vector, and the nature of this vector, which is often of biological origin. Complex tumors that are resistant to current treatments, such as prostate cancer, are most likely to benefit from gene therapy.

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Index Note: Page numbers followed by “f” and “t” refer to figures and tables, respectively.

A Acetylation of P53, 392 Acquired immunodeficiency syndrome (AIDS), 176, 189 Acute renal failure, 325 Adaptive system, 350 Adenovirus, 150, 303
304, 397
405 attachment and entry of virus into host cell, 398
399 early gene transcription, 399
405 generalities about adenoviruses, 303
304 genome replication, 405 structure of, 398 Adenovirus early region 1 (E1A), 210
211 Adenovirus early region 2 (E1B), 211 Adenovirus serotype-5 (Ad serotype-5), 223
225 Adult T cell leukemia/lymphoma (ATLL), 1, 42
43 Adult T cell lymphoma (ATL), 180
181, 214, 228, 235
236 Aflatoxin, 19
20 Africa, gynecomammary cancers in, 294 African 1 group (Af-1 group), 115
116 African 2 group (Af-2 group), 115
116 Aggressive prognosis cancers, 336 Alcohol, 18, 251
252 Alpha genus, 301 Alphaherpesvirinae, 326
327 α-papillomaviruses, 115
116 Alternate reading frame protein (ARFP), 245 American Urological Association, 264
265 Amplification process, 338
340 Androgen receptor (AR), 349
351 homologous recombination defect and BRCA1/BRCA2 mutations, 349
350 in situ hybridization of mRNA, 350
351 Anexelekto receptor (AXL receptor), 253
255 Angiogenesis signaling, 349

Angiotensin converting enzyme 2 (ACE-2), 129 Anti-SARS-CoV-2 vaccine, 135
136 Antigen-presenting cells (APCs), 182
184 Antioncogene genes, 231
232 Antiretroviral therapy (ART), 160, 198 Antiviral therapies, 215, 243 Apolipoprotein B editing complex (APOBEC), 105
106 APOBEC3, 105
106 APOBEC3B, 62
63, 105
106, 281
282 Apoptosis, 394
395 Argonaut 2 protein (AGO2 protein), 76 Asian group (As group), 115
116 Asian-American group (AA group), 115
116 Aspergillus flavus, 19
20 Aspergillus parasiticus, 19
20 Ataxia telangiectasia, 100 Atezolizumab, 253
255

B B cell NHL (B-NHL), 2 B-catenin, 248
251 Basal core promoter (BCP), 14 Basal-like 1 (BL1), 344
345 Basal-like 2 (BL2), 344
345 Benign prostatic hyperplasia (BPH), 264
265 β-catenin, 342 Betaherpesvirinae, 326
327 β-herpesviruses, 311 β-papillomaviruses, 115
116 Betaretrovirus, 57
58, 267 Bevacizumab, 253
255 Birt-Hogg-Dube´ syndrome, 327 BK polyomavirus (BKPyV), 313
319 epidemiology, 313
314 genomic organization of, 316
318 modes of transmission, 314 risk factors, 319

417

418

Index

BK polyomavirus (BKPyV) (Continued) structure of viral particle, 315 viral capsid, 315 virological characteristics, 314
315 BK virus (BKV), 266
267, 305, 311 nephropathy, 319 Bladder cancer, 319 Boceprevir, 248 Body fat, 17 Body mass index (BMI), 17 Bovine leukemia virus, 335
336 BRCA gene mutations, 99
100 Breast cancer, 95, 290
293, 335. See also Triple-negative breast cancer (TNBC) in Africa, 98 anatomy of mammary gland, 336
337 association between human papillomavirus infection and, 341
342 BRCA gene mutations, 99
100 cells, 341
342 dense breasts, 100 epidemiology, 96
98, 337
338 family history, 99 gender, 98
99 genetic disorders, 100
101 genetic mutations, 101 human papillomavirus, 101
103, 338
342 mortality, 336 mouse mammary tumor virus, 103
106 oncogenesis of, 293 personal history, 99 risk factors for, 98
101 Breast cancer type 1 (BRCA1), 96, 99, 211 Breast cancer type 2 (BRCA2), 96, 99, 212 Breast tissue, 341 Breast tumorigenesis, 342 Burkitt lymphoma, 364

C c-Jun N-terminal kinase andactivator protein 1 (JNK/AP-1), 364
365 c-KIT, 348
349 Cabozantinib, 253
255 CAF1, 80 Caf1z. See CAF1 Cancers, 146, 171, 198, 224
225, 227, 229
230, 290 associated with DNA oncoviruses, 159 carcinogenesis, 292 definition of, 291 generalities, 291
294

gynecological and mammary cancers, 292
294 breast cancer, 292
293 cervical cancer, 293 endometrial cancer, 294 ovarian cancer, 293
294 vaginal cancer, 294 vulvar cancer, 294 molecular basis of, 229
230 in Northern Africa, 295
296 by rate of incidence, 297t by rate of mortality, 298t origin of cancer cells, 291
292 P21 and, 395
397 Candida, 237 Canonical Wnt signaling, 342 Capsomeres, 315 Carboxy terminal activation region-2-YYD (CTAR2-YYD), 364
365 Carboxypeptidase, 154 Carcinogenesis, 212
214, 292. See also Oncogenesis gene families involved in, 230
231 oncogenes, 230
231 process, 348
349 Carcinomas, 229
230 Cardiovascular diseases, 290, 325 Catalytic polypeptide 3, 282
283 CCR4-NOT complex, 80 CD4 cells, 191
193 CD4 helper T cells, 350 CD8 helper T cells, 350 CD21 cell receptor, 152
153 Cell cycle, 303
304 arrest, 394
395 apoptosis, 394
395 extracellular signaling, 395 in G1 phase, 394 in G2 phase, 394
395 P53 and cell cycle control, 378
379 regulatory systems, 269, 275 and replication, 116
118 Cells, 29, 129 Cellular localization, 393 Cellular signaling pathways, 233
234 Centers for Disease Control and Prevention (CDC), 147 Central nervous system, 305 Cervarix, 38, 39t, 120, 383 Cervical cancer (CC), 120
121, 293, 296
299, 302
303, 373. See also Gastric cancer (GC)

Index human papillomavirus cervical cancer risk factors, 374 oncogenesis of, 293 viral etiology of, 374
375 Cervical intraepithelial neoplasia (CIN), 115
116, 119
120 CHEK2 gene, 101 Chemotherapy, 133
134, 215, 253
255, 351 Chlamydia trachomatis, 121 Chromatin immunoprecipitation sequencing (ChIP-Seq), 365 Chronic HBV infection, 16 Chronic hepatitis C, 256 Chronic hepatitis viruses, 227 Chronic inflammation, 360
361 Helicobacter pylori inducing aberrant methylation in promoter of tumor suppressor genes via, 362
363 Chronic kidney disease, 331 Chronic liver diseases, 243 Chronic myeloid leukemia, 348
349 Chronic obstructive lung diseases, 290 Cirrhosis, 243 CNOT7. See CAF1 CNOT8. See CAF1 Combination therapy, 248 Condylomas, 50
51 Cooper’s ligament, 336
337 Core protein, 245 Coronavirus disease 2019 (COVID-19), 127
131 impact of COVID-19 pandemic on cancer care, 133
135 in cancer patients, 132
133 on cancer diagnosis, 133 origin, 128
131 Cottontail rabbit papillomavirus (CRPV), 200 Covalently closed circular DNA (cccDNA), 13
14 COVID-19 and Cancer Consortium (CCC-19), 133
134 Cowden syndrome, 101 Coxsackievirus and adenovirus receptor (CAR), 398
399 CREB-binding protein (CBP), 392 Cycle-dependent kinase (CDK), 345
348 Cyclin A, 102
103 Cyclin deoxyribonucleic acid (cDNA), 178 Cyclin E, 102
103 Cyclin-dependent kinase inhibitor 1, 395 Cyclin-dependent kinases (CDKs), 378
379 Cdk2, 185

419

Cyclophosphamide, 215 Cytokeratins, 348
349 Cytokines, 234
235 Cytomegalovirus (CMV), 30
35, 237, 263 and cardiovascular pathology, 34
35 classification, 30 curative treatment, 34 epidemiology, 30 and pathology, 35 prophylactic treatment, 34 relationship between cancer and, 33 replication cycle and steps, 32
33 structural organization, 31
32 transmission, 30
31 viral pathology, 34
35 virological diagnosis, 33
34 DNA amplification reaction, 33 indirect diagnosis, 34 virus research by culture, 33
34 Cytoplasmic processing by dicer, 76

D Deoxyribonucleic acid (DNA), 145
146, 172 amplification reaction, 33 methylation, 302, 360 gastric carcinogenesis, 360
361 oncoviruses, 145 cancers associated with DNA oncoviruses, 159 epidemiology, 147
150 history, discovery, and types, 146 mechanism, 150
152 therapeutic options for DNA oncoviruses, 160 viral proteins, 150 technology, 223
224 Diabetes, 18, 252, 325 Diarrheal diseases, 289 Dicer, cytoplasmic processing by, 76 DiGeorge critical region 8 (DGCR8), 75 Digital rectal examination (DRE), 264
265 Direct-acting antiviral agents (DAA), 248 DKK, 342 DNA damage response (DDR), 283 DNA methyltransferases (DNMTs), 360
361 DNA-binding protein (DBP), 402
403 Docking protein 1 (DOK1), 364
365 Donor-recipient HLA incompatibility, 319 Double-stranded RNA (dsRNA), 172 Double-stranded RNA-binding domain (dsRBD), 76

420

Index

Doxorubicin, 215 Drug, 34, 62, 135 target of HCV, 247
248

E E-cadherin gene, 361
362, 364
365 E1 proteins, 247
248 E2 proteins, 247
248 E5 protein, 150 E6 proteins, 116
118, 150, 376 assessment of joint action of oncoproteins E6and E7, 381
382 consequences of E6 and p53 interaction, 379 interaction between E6 and p53 in cancer pathway, 378
379 E6-associated protein (E6AP), 299
300 E7 protein, 102
103, 116
118, 150, 376 assessment of joint action of oncoproteins E6and E7, 381
382 interaction between E7 and pRb in cancer pathway, 380
381 Endogenous retroviruses, 176 Endometrial cancer, 294 Endoplasmic reticulum (ER), 317 stress, 223
224 Env MMTV, 63 Envelope proteins, 245 Enzyme-linked immunosorbent assay (ELISA), 42, 185 Epidemiology breast cancer, 337
338 of gynecomammary cancers in Africa, 294
296 of HPV and EBV coinfection, 280
281 of PCa, 276
278 Epidermal growth factor receptor (EGFR), 245, 348
349 inhibitors, 348
349 Epithelial-mesenchymal transition (EMT), 83 Epstein-Barr virus (EBV), 1
2, 40, 71
72, 103, 145
147, 197
198, 203
204, 263, 274, 279
280, 303, 311, 325
330, 335
336, 359 association between kidney cancer and, 330
331 coinfection with, 282
283 epidemiology of HPV and EBV coinfection, 280
281 Epstein-Barr virus-encoded microRNAs, 84
86

family, 326
327 generalities, 303 genome, 329 and structure of viruses, 157 genomic organization, 329 history, taxonomy, and classification of, 274
275 host microRNAs associated with EpsteinBarr virus infection, 83
84 implications and associations between HPV and EBV PCa, 281
282 inducing aberrant methylation Helicobacter pylori coinfection with, 366 in promoter of tumor suppressor genes, 363
365 mechanism of action, 152
153 molecular epidemiology of, 275 morphology, 326
330 oncoproteins of, 204 risk factors, 327
328 target cells, 329
330 transmission mode, 327 viral replication, 329 viral structure, 328 virion, 328 Epstein-Barr virus
associated gastric carcinoma (EBVaGC), 83 Escherichia coli, 329 Estrogen receptor-α-dependent gene (ERα gene), 396
397 Eukaryotic translation initiation factor 4F (eIF4F), 78
79 European group (E group), 115
116 European rabbit papillomavirus, 275 Exogenous retroviruses, 176 Exportin 5 nuclear export by, 76 Extracellular signaling, 395

F Factor forkhead box d3 (FOXD3), 361
362 methylation, 361
362 Fas-associated death domain protein (FADD), 81
82 Fibroblast growth factor (FGF), 231 Fibroblast growth factor receptors1
4 (FGFR1
4), 253
255 Flaviviridae, 244 Forkhead box P1 (FOXP1), 85
86 Foscamet (PFA), 34

Index

G Gammaherpesvirinae, 227
228, 274
275, 326
327 γ-papillomaviruses, 115
116 Ganciclovir (GCV), 34 Gardasil, 38, 39t, 120, 383 Gastric cancer (GC), 71, 359, 362
363 DNA methylation in gastric carcinogenesis, 360
361 Helicobacter pylori coinfection with EBV inducing aberrant methylation, 366 and EBV inducing aberrant methylation in promoter of tumor suppressor genes, 361
365 microRNAs in, 80
86 Epstein-Barr virus-encoded microRNAs, 84
86 host microRNAs associated with EpsteinBarr virus infection, 83
84 host microRNAs associated with Helicobacter pylori infection, 81
82 Gastric carcinogenesis, DNA methylation in, 360
361 Gastrointestinal stromal tumors, 348
349 Gene(s), 33, 72, 128, 146, 360 and functions, 210
212 association of genes in oncovirus, 213t BRCA1, 211 BRCA2, 212 E1A, 210
211 E1B, 211 TP53, 212 method of gene regulation, 360 Genetic instability, 231 Genetic mutations, 99 Genital warts. See Condylomas Genitourinary cancers BK polyomavirus, 313
319 involvement of BK in, 319 bladder, 319 prostate, 319 kidney, 320 Polyomaviridae family, 311
312 Genomic DNA amplification techniques, 33 Genomic organization, 329 of BK polyomavirus, 316
318 Gleason scoring system, 265
266 GLOBCAN, 243 Glomerular filtration rate (GFR), 331 Glucose transporter 1 (GLUT-1), 182
184

421

Glycosaminoglycans, 32
33, 156
157, 244
245 Grade Group system, 265
266 GW182 protein, 80 Gynecological cancers, 292
294 Gynecomammary cancers, 291 in Africa, 294 in different continents, 294 epidemiology of, 294
296 molecular oncogenesis of, 296
302 in North Africa incidence and deaths linked to, 295
296 incidence and mortality rates of, 296 oncoviruses associated with, 302
305

H Helicobacter pylori, 71
72, 359 coinfection with EBV inducing aberrant methylation, 366 host microRNAs associated with Helicobacter pylori infection, 81
82 inducing aberrant methylation in promoter of tumor suppressor genes, 361
362 via chronic inflammation, 362
363 Hepacivirus, 244 Heparin-sulfate proteoglycan (HSPG), 182
184, 338
340 Hepatic carcinogenesis, 10 Hepatic tumorigenesis, hepatitis B virus and, 16 Hepatitis B virus (HBV), 2, 5, 11, 145, 148, 172, 197
198, 204
205, 251
252, 274 antiviral treatment, 15 DNA, 11
13 epidemiology, 11 genome and coding genes, 12f genotypes, 13 and hepatic tumorigenesis, 16 hepatocellular carcinoma associated with, 15 mechanism of action, 154 molecular mechanisms of hepato carcinogenesis induced by hepatitis B virus, 16 natural history of hepatitis B virus infection, 14 replication cycle, 13
14 Hepatitis C virus (HCV), 1
2, 5, 146, 148
149, 172, 185
189, 199
200, 207
208, 243, 251
252 carcinogenesis, 248
251

422

Index

Hepatitis C virus (HCV) (Continued) diagnosis, 189, 255
256 drug target of, 247
248 drug and drug target in HCV, 250t fusion and uncoating, 249t host factors, 250t post binding interactions with entry factors, 249t viral assemblies, 250t viral entry, 249t epidemiology and prevalence, 185
186 etiology, 186 life cycle of, 244
246 mechanism, 188 pathogenesis, 188 pathophysiology, 186
187 pathway involved innumerous human metabolic network, 247t progression from hepatitis C virus to hepatocellular carcinoma, 248
252 RNA genome, 245
246 tests for liver damage, 256 hepatocellular carcinoma diagnosis and treatment, 256 transmission, 187 viral genotypes, 251
252 viral proteins, 248
251 Hepatitis E virus (HEV), 22 Hepatitis viruses, 40 Hepatocarcinogenesis molecular mechanisms, 10 of hepato carcinogenesis induced by hepatitis B virus, 16 Hepatocellular carcinoma (HCC), 5
7, 205, 243, 252 anatomopathological characteristics, 7
9 physiopathology, 8 tumor pathology, 8
9 associated with environmental factors, 17 associated with hepatitis B virus, 15 diagnosis and treatment, 256 drugs and drug targets in, 253
255, 255t epidemiology and etiological factors, 6
7 incidence, 6
7 hepatitis B virus, 11 metabolic and environmental risk factors, 17
19 metabolic pathways involved in HCC, 254t molecular mechanism of hepatocarcinogenesis, 10 mortality, 7

nature and history of liver carcinogenesis, 9
10 nutritional risk factors for, 19
21 prevention of risk factors, 21
22 progression from hepatitis C virus to, 248
252 synergy between hepatitis B virus and environmental factors in etiology, 22 virological data, 11
14 Heritable papillary carcinoma, 327 Herpesviridae, 227
228, 274
275, 303, 326
327, 329
330 Herpesvirus 8, 311 Herpesviruses, 263 Heterodimers, 341
342 High-risk genotypes (HR genotypes), 269
270 High-risk oncogenic genital HPVs. (HRHPV), 115
116, 293, 373
374 Histone deacetylase 1 (HDAC1), 364
365 Histone deacetylase 3 (HDAC3), 365 Homodimers, 341
342 HTLV-1 associated myelopathy (HAM), 207, 228 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), 181, 214 Human colonic adenocarcinoma cells (Caco-2 cells), 33 Human cytomegalovirus (HCMV), 146, 311 Human herpes simplex virus type 2 (HSV-2), 263 Human herpesvirus, 274 Human herpesvirus 4 (HHV-4), 274
275 Human herpesvirus 8 (HHV-8), 145, 149, 197
200, 205
206, 227
228, 263 and associated tumors, 206, 233
235 genome and structure of viruses, 158 HHV-8-related diseases, 235 mechanism of action, 154
155 oncogenic viral genes and tumorigenesis, 233
235 Human immunodeficiency virus (HIV), 1
2, 189
193, 251
252, 289 epidemiology and prevalence, 189 etiology, 189 evaluation and diagnosis, 193 mechanisms underlying HIV-1 pathogenicity in epithelial cells, 191
193 pathophysiology, 189
190 replication, 190
191 transmission, 190

Index Human leukemia virus (HTLV), 172 Human leukocyte antigen (HLA), 330 Human mammary tumor virus (HMTV), 303 Human oncogenic RNA viruses, 274 Human papillomavirus (HPV), 1, 35
36, 40, 49, 96, 145, 147
148, 197
198, 206
207, 263, 274
275, 293, 302
303, 311, 335
336, 338
342, 373. See also Mouse mammary tumor virus (MMTV) assessment of joint action of oncoproteins E6and E7, 381
382 association between human papillomavirus infection and breast cancer, 341
342 biology of papillomavirus, 375
378 structural and genomic organization, 375 viral infection and expression of viral oncoproteins, 376
378 breast cancer, 101
103 cancer, 55
57 cervical cancer, 120
121 risk factors, 374 classification, 50
51, 51t coinfection with, 282
283 consequences of E6 and p53 interaction, 379 epidemiology, 35
36 of HPV and EBV coinfection, 280
281 evolution of human papillomavirus infection, 55 genome and structure of viruses, 158 history, 50 taxonomy, and classification of, 274
275 HPV 16, 49
50 HPV 18, 49
50 implications and associations between HPV and EBV PCa, 281
282 infection, 50
57, 269
270 cell cycle and replication, 116
118 integration of human papillomavirus into breast cells, 53
55 cellular response, 54 hormonal response, 54 immune response, 53
55 mode of contamination, 53 interaction between E6 and p53 in cancer pathway, 378
379 P53 and cell cycle control, 378
379 interaction between E7 and pRb in cancer pathway, 380
381 mechanism of action, 153
154

423

mode of transmission, 52 molecular architecture, 116 molecular epidemiology, 275 oncogenesis, 56
57 oncovirus, 223
224 pathophysiology, evolution, and natural history, 119
120 prevention, 57 effectiveness of human papillomavirus vaccination, 57 and prostate cancer, 269
270, 278
279 recent progress, 224 route of human papillomavirus infection, 338
340 structure, 51
52 transmission mode and risk factors, 118
119 vaccination, 382
383 viral cycle, 52
53, 376
378 assembly and release of newly formed virions, 378 encounter and attachment of virus and target cell, 377 entry and decapsidation, 377 expression of viral genes and amplification of viral genome, 378 viral etiology of cervical cancer, 374
375 virology, 113
116 epidemiology and taxonomic classification, 113
116 genotypes, 115t Human polyomavirus BK (BKV), 319 Human polyomavirus JC (JCPyV), 305 Human polyomaviruses (HPyVs), 304
305. See also BK polyomavirus (BKPyV) generalities, 304
305 BK virus, 305 JC virus, 305 MCPyV, 305 HPyV1, 314
315 Human T cell lymphotropic virus 1 (HTLV1), 1, 40, 146, 149, 180
185, 207, 228 diagnosis, 42, 185 epidemiology, 41 and prevalence, 180 etiology, 180
181 HTLV-1-related tropical myelopathy and spastic paraparesis, 42 mechanism, 184
185 molecular aspects of human T-lymphotropic virus type 1 and associated tumors, 235
237 diseases associated with HTLV-1, 237

424

Index

Human T cell lymphotropic virus 1 (HTLV-1) (Continued) HTLV-1 oncogenic viral genes and tumorigenesis, 236
237 pathophysiology, 181 replication, 182
184 transmission, 41
42, 181
182 treatment, 42 viral pathology, 43 Human T-cell lymphotropic virus (HTLV), 200, 311 Human T-lymphotropic virus type 2 (HTLV-2), 40 Human tumors, 311 Hyperinsulinemia, 18 Hyperlipidemia, 17 Hypertension, 325

I Icosahedral capsid, 32 IkB kinase-ε, 81
82 Immune response, 133 Immune system, 224
225, 282
283 Immunoglobulin G (IgG), 34 Immunohistochemistry (IHC), 345
348 Immunomodulatory (IM), 344
345 Immunoreceptor tyrosine-based activation pattern (ITAM), 63 Immunotherapy, 135, 351 In situ hybridization (ISH), 330
331 mRNA, 350
351 In vivo gene therapy with P53 or P21 adenovirus for prostate cancer, 405
407 Innate immune system, 350 Integrin α6, 338
340 Interferon (IFN), 247
248 Interferon alpha (IFN-α), 215 Interleukin 1 beta (IL-1β), 81, 362
363 Interleukin 6 (IL-6), 234
235 Internal ribosomal entry site (IRES), 245 International Agency for Research on Cancer (IARC), 269
270, 290
291, 296 International Committee on Taxonomy of Viruses (ICTV), 127 Intralesional chemotherapy, 215

J Janus kinase/signal transducers and activators of transcription 3 (JAK/STAT3), 364
365 JC virus (JCV), 305, 311, 313 Juices, 21

K Kaposi sarcoma (KS), 199
200, 233, 290
291 Kaposi sarcoma
associated herpesvirus (KSHV), 40, 146, 172, 228
229, 274 Ki-67, 345
348 Kidneys cancer, 320, 325 association between kidney cancer and Epstein-Barr virus, 330
331 Kinesin-like protein (KIP 1), 102
103 KIT, 253
255 Koilocyte, 338
340 Koilocytosis, 338
340

L L1 protein, 116
118 L2 protein, 116
118 Lactiferous sinus, 336
337 Laryngeal cancer, 296 Lectins, 130 Lenvatinib, 253
255 Li-Fraumeni syndrome, 100 Lifestyle diseases, 252 Lin-4, 72
73 Lipids, 20
21 Liver biopsy, 256 nature and history of liver carcinogenesis, 9
10 tests for liver damage, 256 transplant surgery, 256 LKB1 gene. See STK11 gene Long control region (LCRs), 115
116 Long terminal repeats (LTRs), 58, 103
104, 178, 267 Low-risk oncogenic HPVs. (LR-HPV), 115
116 Lung cancer, 97, 276 Lymphocryptovirus, 274
275, 326
327 Lytic replication, 205
206

M Macrophage inflammatory protein 1 alpha (MIP-1α), 234
235 Magnetic resonance elastography, 256 Malignant tumors, 227, 291 Mammary cancers, 292
294 Mammary gland, anatomy of, 336
337 Mammary tumorigenesis, 63 MDM2, 392
393 Membrane glycoprotein, 128

Index Merkel cell polyomavirus (MCPyV), 145, 149
150, 199
200, 208
209, 305 genome and structure of viruses, 158 mechanism of action, 156
157 Mesenchymal stem-like (MSL), 344
345 Mesenchymal-epithelial transition factor (MET), 253
255 Messenger RNAs (mRNAs), 32
33 Metastatic mechanisms, 348
349 Methyl CpG-binding protein 2 (MeCP2), 364
365 Microprocessor, 75 MicroRNAs (miRNAs), 72 biogenesis, 74
80 discovery of first, 72
73 in gastric cancer, 80
86 genomic localization, 74 mechanism of action, 77
80 microRNA-mediated gene silencing via RNA-induced silencing complex, 78 miR-21, 81
82 miR-124, 81 miR-223, 81
82 miR-BARTs, 85
86 nomenclature, 73
74 primary transcripts, 74
75 maturation, 75
77 target mRNA translation repression, 78
80 Microsomal triglyceride transfer protein, 246 Minerals, 21 Minor proteins, 315 miRNP, 76
77 Mogamulizumab, 198 Molecular hybridization techniques, 330
331 Molecular oncogenesis of gynecomammary cancer, 296
302 Monoclonal antibodies, 348
349 Montgomery’s tubercle, 336
337 Mouse mammary tumor virus (MMTV), 49, 96, 171, 263, 267
268, 335
336 breast cancer, 103
106 cancer, 62
63 history, 57
58 infection, 57
63 in breast cells leading to cancer, 62
63 integration of mouse mammary tumor virus into breast cells, 61
62 integrating mouse mammary tumor virus into human genome, 61
62 pathogenicity of virus, 61 and mammary tumorigenesis, 63 mechanisms of MMTV oncogenesis in human breast cancer, 105
106

425

MMTV-like DNA, 49
50 mode of transmission, 58
60 structure, 58 viral cycle, 60
61 Mouse polyomavirus, 312 Mouse primary embryonic fibroblasts (MEF), 283 MRI, 256 Mucous membranes, 338
340 Multicentric castleman disease (MCD), 205, 227
228 Murine leukemia virus, 172

N N-myc downstream regulated gene 1 (NDRG1), 85
86 Nasopharyngeal cancer (NPC), 84, 199
200, 205 Natural killer cells (NK cells), 203
204 Neoplasms, 227, 291 Neovirions, 32
33 Neuroendocrine tumors, 264 Neuropil 1 (NRP1), 130 Neuropilin 1, 182
184 Neutralizing antibodies, 2 Niemann-Pick C1-Like1 (NPC1L1), 245 Nivolumab, 160 Non-Hodgkin’s lymphoma (NHL), 1
2 Nonalcoholic fatty liver disease (NAFLD), 17, 252 Nonalcoholic steatohepatitis, 252 Noncancerous tissues, 360
361 Noncommunicable diseases (NCDs), 289
290 Nonspecific viral receptors, 130 Nonstructural proteins, 245 North Africa incidence and deaths linked to gynecomammary cancers in, 295
296 incidence and mortality rates of gynecomammary cancers in, 296 top ten cancers in, 295
296, 297t NS2 peptide, 247
248 NS3 protein, 247
248 Nuclear export by exportin 5, 76 Nuclear factor kappa B (NF-κB), 234
235, 364
365 pathway, 236
237 Nuclear hormone receptors, 341
342 Nucleocapsid protein, 128 Nutritional risk factors for hepatocellular carcinoma, 19
21

426

Index

O

P

Obesity, 5, 17, 252 Occludin, 244
245 Oncogenes, 146, 178, 230
231, 230t Oncogenesis, 210 consequences of viral infection, 229 discovery of oncogenic viruses, 228
229 gene families involved in carcinogenesis, 230
231 infections, 229 molecular aspects of human herpesvirus 8 and associated tumors, 233
235 human T-lymphotropic virus type 1 and associated tumors, 235
237 molecular basis of cancer, 229
230 oncogenic viruses, 232
233 tumor suppressor or antioncogene genes, 231
232 Oncogenic DNA viruses, 145 Oncogenic infections, 197
198 Oncogenic viruses, 1, 228, 232
233, 273
274 discovery of, 228
229 Oncohematological diseases, 348
349 Oncolytic virotherapy, 198, 216, 223
224 Oncoproteins, 102, 116 of Epstein-Barr virus, 204 Oncovirus(es), 145, 171, 198, 199f associated with gynecomammary cancer, 302
305 adenoviruses, 303
304 EBV, 303 HMTV, 303 human papillomavirus, 302
303 human polyomaviruses, 304
305 classification of, 203
209, 209t EBV, 203
204 HBV, 204
205 HCV, 207
208 HHV-8, 205
206 human papillomavirus, 206
207 human T-cell lymphotropic virus 1, 207 MCPyV, 208
209 discovery and timeline, 200, 201t mechanism, 201
202 Open reading frames (ORFs), 11
13, 205
206 Orthoretrovirinae subfamily, 267 Ovarian cancer, 293
294, 325 Overall survival (OS), 237

P21 protein, 102
103, 395
397 P21 and cancer, 395
397 in vivo gene therapy with P53 or P21 adenovirus for prostate cancer, 405
407 p27 protein, 102
103 p53 protein, 201, 345
348, 388
393 and cell cycle control, 378
379 cellular localization, 393 consequences of E6 and p53 interaction, 379 functions, 393 gatekeeper, 389
390 history, 388
389 interaction between E6 and p53 in cancer pathway, 378
379 regulation, 391
393 acetylation of P53, 392 interaction of P53
MDM2, 392
393 modifications of P53, 392 phosphorylation of P53, 391
392 ubiquitination of P53, 392 structure, 390
391 in vivo gene therapy with P53 or P21 adenovirus for prostate cancer, 405
407 PALB2 gene, 101 Papilloma Trial against Cancer in Young Adults (PATRICIA), 120
121 Papillomaviridae, 269, 275, 300
301 Papillomavirus, 35
40, 300
301. See also Cytomegalovirus (CMV) classification, 35 epidemiology of human papillomavirus, 35
36 genomic organization, 36 preventive treatment, 38 relationship between cancer and, 38 structural organization, 36 transmission, 36 viral cycle, 37 viral pathology, 39
40 Papovaviridae, 275 Partner of Drosha (Pasha). See DiGeorge critical region 8 (DGCR8) Pathology of tumor, 8
9 PAZ domain, 76 Penile intraepithelial neoplasia (PIN), 119
120 Peutz-Jeghers syndrome, 101 Phosphatidylinositol 3-kinase (PI3K), 364
365 Phosphatidylserine receptors, 130

Index Phospholipases C (PKC), 231 Phosphoproteins, 32 Phosphorylation of P53, 391
392 Physical activity, lack of, 19 Placental growth factor, 349 Platelet-derived growth factor receptor (PDGF-R), 253
255 PDGF receptor α, 253
255 Platinum chemotherapy, 349
350 Pneumocystis jirovecci, 237 Polycombic targets, 302 Polymerase chain reaction (PCR), 33, 189, 330
331, 335
336 Polymerase III, 74
75 Polyomaviridae, 305, 311
312, 319 History of discovery, 312 Polyomaviruses, 311
312, 316
317 BKV, 263 hominis 1, 266
267 Pralatrexate, 198 pRb in cancer pathway, 380
381 Precursor miRNA (pre-miRNA), 73
74 training, 75 Prednisolone, 215 Prednisone, 215 Pregenomic RNA (pgRNA), 13
14 Primary effusion lymphoma (PEL), 205 Primary liver cancer, 6 Primary miRNA (pri-miRNA), 74
75 Pro-oncogenes, 115
116 Proapoptotic p53 modulator of apoptosis (PUMA), 84
85 Processed meats, 20 Productive infection, 39 Programmed cell death protein 1 (PD-1), 351 Proliferative inflammatory atrophy (PIA), 319 Prophylactic vaccination, 382
383 Prostate cancer (PCa), 263
266, 273
274, 290
291, 319, 387 coinfection with HPV and EBV, 282
283 detection, diagnosis, and staging, 264
266, 265t EBV, 279
280 epidemiology, 266, 276
278 of HPV and EBV coinfection, 280
281 history, taxonomy, and classification of HPV and EBV, 274
275 human papillomavirus, 269
270, 278
279 implications and associations between HPV and EBV PCa, 281
282 molecular epidemiology of HPV and EBV associated with, 275 viral infections as risk factor for, 266
270

427

in vivo gene therapy with P53 or P21 adenovirus for, 405
407 Prostate gland, 264 Prostate tissues, 263 Prostate tumorigenesis process, 263 Prostate-specific antigen (PSA), 264
265 Prostatic intraepithelial neoplasia (PIN), 264 Protease inhibitors, 248 Protein membrane latent 1 (LPM-1), 283 Proteins, 150, 311 NS5A, 246 Proto-oncogenes, 178
179, 230
232 Protuberant dermatofibrosarcoma, 348
349 Proviruses, 176 Public Health France, 330

R Rabbit papillomavirus, 312 Radiotherapy, 215 Ranimustine, 215 Recombinant immunoblot assay, 189 Red meats, 20 Regorafenib, 253
255 Renal cell carcinoma, 325 Respiratory diseases, 289 RET, 253
255 Retinoblastoma (RB), 201 protein, 248
251 susceptibility gene, 380 Retroviridae, 267 Retroviruses, 172, 182
184 Reverse transcriptase, 178, 248
251 Reverse transcription, 178 Rhadinovirus, 227
228 Ribonucleic acid (RNA), 172 Risk factors, 17
19, 289 for EBV, 327
328 RNA oncogenic virus, 40
43 classification, 40 human T-lymphotropic virus type 1, 40 RNA oncoviruses endogenous and exogenous retroviruses, 176 hepatitis C virus, 185
189 human immunodeficiency virus, 189
193 human T cell lymphotropic virus 1, 180
185 proto-oncogene, 178
179 reverse transcription, 178 timeline of oncoviruses, 174
175 and variants, 172
174 viral carcinogenesis, 177
178 virus involvement in cancer, 171
172

428

Index

RNA-induced silencing complex formation, 76
77 RNase III Drosha, 75 Rooster crests. See Condylomas

S Sarcomas, 264 Scavenger receptor class B member 1 (SRB1), 244
245 Semliki Forest virus (SFV), 223
224 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 2, 127 coronavirus disease, 128
131 factors affecting pathogenesis of virus, 131
133 age, 132
133 gender, 131 global epidemiology, 130
131 structure and genomic organization, 128
129 vaccines in cancer patients, 136 viral cycle, 129
130 Sexually transmitted infection (STI), 35
36 SFRP, 342 Signal transduction pathways, 345 Simian virus 40 (SV40), 311, 313 Single-stranded RNA (ssRNA), 172 Skin, 338
340 tropism, 301 Sma-and Mad-related protein 2 (SMAD2), 81
82 Small cell carcinomas, 264 Small envelope glycoprotein, 128 Small T antigen (t-Ag), 311 Smoking, 251
252 Spermine oxidase (SMOX), 81 Spike glycoprotein, 128 Spumaviruses, 176 STK11 gene, 101 Stomach cancer, 71 Strongyloides stercoralis, 237 Structural HCV core protein, 247
248 Sugary drinks, 21 Superantigens (SAgs), 58, 104
105 Surface proteins (SU proteins), 60 Surgery, 134

T T antigen (T-Ag), 311 T-cell leukemia (TCL), 40 T4 lymphocyte, 190
191

Telaprevir, 248 Telomerase, 248
251 Tetraspanin, 244
245 TMPRSS2 protease, 130 Tobacco, 18 Toll-like receptor-3 (TLR-3), 247
248 Toxicology, 172 Trans-activating RNA-binding protein (TRBP), 76 Transcription unit (Tu), 74 Transforming growth factor beta (TGF-β), 233
234, 248
251 TGF-β1, 362
363 Transient elastography, 256 Transitional cell carcinomas, 264 Transmembrane proteins (TM proteins), 60 Triple-negative breast cancer (TNBC), 336, 342
351 AR, 349
351 epidemiology, 344
345 main biomarkers with impact on prognosis or survival, 346t epidermal growth factor receptor, c-KIT, and cytokeratins, 348
349 TP53 gene, p53 protein, and Ki-67, 345
348 VEGF, 349 Tropical spastic paraparesis (TSP), 207 Tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM), 228 Tumor necrosis factor alpha (TNF-α), 81 Tumor protein 53 gene (TP53 gene), 212, 248
251, 345
348 Tumor-infiltrating lymphocytes (TILs), 350 Tumor(s), 35, 49, 80
81, 132
133, 227, 229
230, 273
275, 304 cells, 8
9, 223
224, 350 EBV inducing aberrant methylation in promoter of, 363
365 Helicobacter pylori inducing aberrant methylation in promoter of, 361
362 oncogenic viruses, 311 suppressor genes, 202, 231
232, 232t, 345
348, 360
361, 380 via chronic inflammation, 362
363 viruses, 197 Tumorigenesis, 197
198, 292, 345 Type 2 diabetes, 5, 290 Tyrosine kinase inhibitors (TKI), 348
349

Index

U U.S. Centers for Disease Control and Prevention (CDC), 243 U.S. Food and Drug Administration, 223
224 Ubiquitination of P53, 392

V Vaccination, 382
383 Vaccinia virus (VV), 223
225 Vacuolating virus, 312 Vaginal cancer, 294 Vascular endothelial growth factor (VEGF), 349 VEGF-A, 349 VEGF-B, 349 VEGF-C, 349 VEGF-D, 349 VEGF-E, 349 Vascular endothelial growth factor receptor (VEGFR-2/3), 253
255 Very low-density lipoprotein (VLDL), 246 Vincristine, 215 Vindesine, etoposide, carboplatin, and prednisolone (VECP), 215 Viral capsid, 13
14, 315 Viral carcinogenesis, 177
178 Viral cyclin, 234
235 Viral FLICE inhibitor protein (v-flip), 205
206 Viral G protein
coupled receptor encoded by HHV-8 (v-GPCR), 234
235 Viral genome, 317
318 Viral IFN regulatory factor (v-IRF-1), 235 Viral infections, 376
378 consequences of, 229 as risk factor for prostate cancer, 266
270 human papillomavirus and prostate cancer, 269
270 mouse mammary tumor virus, 267
268 Viral latency, 232
233 Viral nucleotide, 247
248 Viral oncoproteins expression, 376
378 Viral pathogenesis, 247
248 Viral pro-oncogenes, 116 Viral protein R (vpr), 191
193 Viral proteins, 32
33, 150, 151t VP1, 156
157 VP2, 156
157 VP3, 156
157

429

Viral replication, 329 Viral RNAs, 13
14 Viral trans-activator (viral tat), 191
193 Virion replication process, 245
246 Virological data, 11
14 viral structure, 11
12 Virology, 180
181 Virostatic drugs, 34 Virotherapy, 223
224 Virus-like particles (VLPs), 383 Viruses, 223
224, 293 adenoviruses, 303
304 causes and prevention, 212
214 classification of oncoviruses, 203
209 cytomegalovirus, 30
35 discovery of oncovirus and timeline, 200, 201t epidemiology, 199
200 genes associated with oncogenes and virus tumor complications, 210
212 genes and functions, 210
212 mechanism of oncovirus, 201
202 oncovirus and prevalence, 198 papillomavirus, 35
40 RNA oncogenic virus, 40
43 therapies and treatment, 214
215 Vitamin K epoxide reductase complex subunit 1 (VKORC1), 235 Vitamins, 21 Von Hippel-Lindau disease (VHL disease), 327 Vulvar cancer, 294

W World Cancer Research Fund/American Institute for Cancer Research (WCRF/ AICR), 17 World Health Organization (WHO), 2, 127, 147
148, 243, 276, 289

X Xenotropic murine leukemia virus
related virus (XMRV
related virus), 263

Y YM155 inhibitor, 160